Cetp inhibitors

ABSTRACT

Compounds having the structures of Formula I, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors, and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis: 
     
       
         
         
             
             
         
       
     
     In the compounds of Formula I, B or R 2  is a phenyl group which has an ortho aryl, heterocyclic, benzoheterocyclic or benzocycloalkyl substituent, and one other position on the 5-membered ring has an aromatic, heterocyclic, cycloalkyl, benzoheterocyclic or benzocycloalkyl substituent connected directly to the ring or attached to the ring through a —CH 2 —.

FIELD OF THE INVENTION

This invention relates to a class of chemical compounds that inhibitcholesterol ester transfer protein (CETP) and therefore may have utilityin the treatment and prevention of atherosclerosis.

BACKGROUND OF THE INVENTION

Atherosclerosis and its clinical consequences, coronary heart disease(CHD), stroke and peripheral vascular disease, represent a trulyenormous burden to the health care systems of the industrialized world.In the United States alone, approximately 13 million patients have beendiagnosed with CHD, and greater than one half million deaths areattributed to CHD each year. Further, this toll is expected to grow overthe next quarter century as an epidemic in obesity and diabetescontinues to grow.

It has long been recognized that in mammals, variations in circulatinglipoprotein profiles correlate with the risk of atherosclerosis and CHD.The clinical success of HMG-CoA Reductase inhibitors, especially thestatins, in reducing coronary events is based on the reduction ofcirculating Low Density Lipoprotein cholesterol (LDL-C), levels of whichcorrelate directly with increased risk for atherosclerosis. Morerecently, epidemiologic studies have demonstrated an inverserelationship between High Density Lipoprotein cholesterol (HDL-C) levelsand atherosclerosis, leading to the conclusion that low serum HDL-Clevels are associated with an increased risk for CHD.

Metabolic control of lipoprotein levels is a complex and dynamic processinvolving many factors. One important metabolic control in man is thecholesteryl ester transfer protein (CETP), a plasma glycoprotein thatcatalyzes the movement of cholesteryl esters from HDL to the apoBcontaining lipoproteins, especially VLDL (see Hesler, C. B., et. al.(1987) Purification and characterization of human plasma cholesterylester transfer protein. J. Biol. Chem. 262(5), 2275-2282)). Underphysiological conditions, the net reaction is a heteroexchange in whichCETP carries triglyceride to HDL from the apoB lipoproteins andtransports cholesterol ester from HDL to the apoliprotein.

In humans, CETP plays a role in reverse cholesterol transport, theprocess whereby cholesterol is returned to the liver from peripheraltissues. Intriguingly, many animals do not possess CETP, includinganimals that have high HDL levels and are known to be resistant tocoronary heart disease, such as rodents (see Guyard-Dangremont, V., et.al., (1998) Phospholipid and cholesteryl ester transfer activities inplasma from 14 vertebrate species. Relation to atherogenesissusceptibility, Comp. Biochem. Physiol. B Biochem. Mol. Biol. 120(3),517-525). Numerous epidemiologic studies correlating the effects ofnatural variation in CETP activity with respect to coronary heartdisease risk have been performed, including studies on a small number ofknown human null mutations (see Hirano, K.-I., Yamashita, S. andMatsuzawa, Y. (2000) Pros and cons of inhibiting cholesteryl estertransfer protein, Curr. Opin. Lipidol. 11(6), 589-596). These studieshave clearly demonstrated an inverse correlation between plasma HDL-Cconcentration and CETP activity (see Inazu, A., et. al. (2000)Cholesteryl ester transfer protein and atherosclerosis, Curr. Opin.Lipidol. 11(4), 389-396), leading to the hypothesis that pharmacologicinhibition of CETP lipid transfer activity may be beneficial to humansby increasing levels of HDL-C while lowering those of LDL.

Despite the significant therapeutic advance that statins such assimvastatin (ZOCOR®) represent, statins only achieve a risk reduction ofapproximately one-third in the treatment and prevention ofatherosclerosis and ensuing atherosclerotic disease events. Currently,few pharmacologic therapies are available that favorably raisecirculating levels of HDL-C. Certain statins and some fibrates offermodest HDL-C gains. Niacin, which provides the most effective therapyfor raising HDL-C that has been clinically documented, suffers frompatient compliance issues, due in part to side effects such as flushing.An agent that safely and effectively raises HDL cholesterol levels cananswer a significant, but as yet unmet medical need by offering a meansof pharmacologic therapy that can significantly improve circulatinglipid profiles through a mechanism that is complementary to existingtherapies.

New classes of chemical compounds that inhibit CETP are beinginvestigated at several pharmaceutical companies or are in clinicaltrials. No CETP inhibitors are currently being marketed. New compoundsare needed so that one or more pharmaceutical compounds can be foundthat are safe and effective. The novel compounds described herein arevery potent CETP inhibitors. Some structurally similar compounds arefound in WO2003/032981.

SUMMARY OF THE INVENTION

Compounds having Formula I, including pharmaceutically acceptable saltsof the compounds, are CETP inhibitors, having the utilities describedbelow:

In the compounds of Formula I,

Y is selected from —C(═O)— and —(CRR¹)—;

X is selected from —O—, —NH—, —N(C₁-C₅alkyl)-, and —(CRR⁶)—;

Z is selected from —C(═O)—, —S(O)₂—, and —C(═N—R⁹)—, wherein R⁹ isselected from the group consisting of H, —CN, and —C₁-C₅alkyl optionallysubstituted with 1-11 halogens;

Each R is independently selected from the group consisting of H, —C₁-C₅alkyl, and halogen, wherein —C₁-C₅ alkyl is optionally substituted with1-11 halogens;

B is selected from the group consisting of A¹ and A², wherein A¹ has thestructure:

R¹ and R⁶ are each independently selected from H, —C₁-C₅ alkyl, halogen,and —(C(R)₂)_(n)A², wherein —C₁-C₅ alkyl is optionally substituted with1-11 halogens;

R² is selected from the group consisting of H, —C₁-C₅ alkyl, halogen,A¹, and —(C(R)₂)_(n)A², wherein —C₁-C₅ alkyl is optionally substitutedwith 1-11 halogens;

Wherein one of B and R² is A¹; and one of B, R¹, R², and R⁶ is A² or—(C(R)₂)_(n)A²; so that the compound of Formula I comprises one group A¹and one group A²;

A³ is selected from the group consisting of:

-   -   (a) an aromatic ring selected from phenyl and naphthyl;    -   (b) a phenyl ring fused to a 5-7 membered non-aromatic        cycloalkyl ring, which optionally comprises 1-2 double bonds;    -   (c) a 5-6-membered heterocyclic ring having 1-4 heteroatoms        independently selected from N, S, O, and —N(O)—, and optionally        also comprising 1-3 double bonds and a carbonyl group, wherein        the point of attachment of A³ to the phenyl ring to which A³ is        attached is a carbon atom; and    -   (d) a benzoheterocyclic ring comprising a phenyl ring fused to a        5-6-membered heterocyclic ring having 1-2 heteroatoms        independently selected from O, N, and S, and optionally also        having 1-2 double bonds (in addition to the double bond of the        fused phenyl ring) wherein the point of attachment of A³ to the        phenyl ring to which A³ is attached is a carbon atom;

A² is selected from the group consisting of:

-   -   (a) an aromatic ring selected from phenyl and naphthyl;    -   (b) a phenyl ring fused to a 5-7 membered non-aromatic        cycloalkyl ring, which optionally comprises 1-2 double bonds;    -   (c) a 5-6-membered heterocyclic ring having 1-4 heteroatoms        independently selected from N, S, O, and —N(O)—, and optionally        also comprising 1-3 double bonds and a carbonyl group;    -   (d) a benzoheterocyclic ring comprising a phenyl ring fused to a        5-6-membered heterocyclic ring having 1-2 heteroatoms        independently selected from O, N, and S, and optionally also        having 1-2 double bonds (in addition to the double bond of the        fused phenyl ring); and    -   (e) a —C₃-C₈ cycloalkyl ring optionally having 1-3 double bonds;

wherein A³ and A² are each optionally substituted with 1-5 substituentgroups independently selected from R^(a);

Each R^(a) is independently selected from the group consisting of —C₁-C₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl optionallyhaving 1-3 double bonds, —OC₁-C₆alkyl, —OC₂-C₆ alkenyl, —OC₂-C₆ alkynyl,—OC₃-C₈ cycloalkyl optionally having 1-3 double bonds, —C(═O)C₁-C₆alkyl,—C(═O)C₃-C₈ cycloalkyl, —C(═O)H, —CO₂H, —CO₂C₁-C₆alkyl,—C(═O)SC₁-C₆alkyl, —OH, —NR³R⁴, —C(═O)NR³R⁴, —NR³C(═O)OC₁-C₆ alkyl,—NR³C(═O)NR³R⁴, —S(O)_(x)C₁-C₆ alkyl, —S(O)_(y)NR³R⁴, —NR³S(O)_(y)NR³R⁴,halogen, —CN, —NO₂, and a 5-6-membered heterocyclic ring having 1-4heteroatoms independently selected from N, S, and O, said heterocyclicring optionally also comprising a carbonyl group and optionally alsocomprising 1-3 double bonds, wherein the point of attachment of saidheterocyclic ring to the ring to which R^(a) is attached is a carbonatom, wherein said heterocyclic ring is optionally substituted with 1-5substituent groups independently selected from halogen, —C₁-C₃ alkyl,and —OC₁-C₃ alkyl, wherein —C₁-C₃ alkyl and —OC₁-C₃ alkyl are optionallysubstituted with 1-7 halogens;

wherein for compounds in which R^(a) is selected from the groupconsisting of —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₃-C₈cycloalkyl optionally having 1-3 double bonds, —C₁-C₆alkyl, —OC₂-C₆alkenyl, —OC₂-C₆ alkynyl, —OC₃-C₈ cycloalkyl optionally having 1-3double bonds, —C(═O)C₁-C₆alkyl, —C(═O)C₃-C₈ cycloalkyl, —CO₂C₁-C₆alkyl,—C(═O)SC₁-C₆alkyl, —NR³C(═O)OC₁-C₆ alkyl, and —S(O)_(x)C₁-C₆ alkyl,R^(a) is optionally substituted with 1-15 halogens and is optionallyalso substituted with 1-3 substituent groups independently selected from(a) —OH, (b) —CN, (c) —NR³R⁴, (d) —C₃-C₈ cycloalkyl optionally having1-3 double bonds and optionally substituted with 1-15 halogens, (e)—OC₁-C₄alkyl optionally substituted with 1-9 halogens and optionallyalso substituted with 1-2 substituent groups independently selected from—OC₁-C₂ alkyl and phenyl, (f) —OC₃-C₈ cycloalkyl optionally having 1-3double bonds and optionally substituted with 1-15 halogens, (g) —CO₂H,(h) —C(═O)CH₃, (i) —CO₂C₁-C₄alkyl which is optionally substituted with1-9 halogens, and (j) phenyl which is optionally substituted with 1-3groups independently selected from halogen, —CH₃, —CF₃, —OCH₃, and—OCF₃;

with the proviso that when B is A¹, and X and Y are —CH₂—, and Z is—C(═O)—, and R² is phenyl which has a substituent R^(a) in the4-position, wherein R^(a) is —OC₁-C₆alkyl which is optionallysubstituted as described above, then there are no other R^(a)substitutents on R² in which R^(a) is selected from —OH, —OC₁-C₆alkyl,—OC₂-C₆ alkenyl, —OC₂-C₆ alkynyl, and —OC₃-C₈ cycloalkyl optionallyhaving 1-3 double bonds, all of which are optionally substituted asdescribed above.

n is 0 or 1;

p is an integer from 0-4;

x is 0, 1, or 2;

y is 1 or 2;

R³ and R⁴ are each independently selected from H, —C₁-C₅ alkyl,—C(═O)C₁-C₅ alkyl and —S(O)_(y)C₁-C₅ alkyl, wherein —C₁-C₅ alkyl in allinstances is optionally substituted with 1-11 halogens; and

R⁵ is selected from the group consisting of H, —OH, —C₁-C₅ alkyl, andhalogen, wherein —C₁-C₅ alkyl is optionally substituted with 1-11halogens.

In the compounds of Formula I and in subsequent compounds, alkyl,alkenyl, and alkynyl groups can be either linear or branched, unlessotherwise stated.

DETAILED DESCRIPTION OF THE INVENTION

Many of compounds of this invention have a structure in accordance withFormula Ia, written below, or a pharmaceutically acceptable saltthereof:

Many compounds of the invention have the structure of Formula Ib, or apharmaceutically acceptable salt thereof:

Many other compounds have the structure of Formula Ic or apharmaceutically acceptable salt thereof:

Still other compounds of the invention have a structure in accordancewith Formula Id, or a pharmaceutically acceptable salt thereof:

In a subset of the compounds of Formula I,

Each R^(a) is independently selected from the group consisting of —C₁-C₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl optionallyhaving 1-3 double bonds, —OC₁-C₆alkyl, —OC₂-C₆ alkenyl, —OC₂-C₆ alkynyl,—OC₃-C₈ cycloalkyl optionally having 1-3 double bonds, —C(═O)C₁-C₆alkyl,—C(═O)C₃-C₈ cycloalkyl, —C(═O)H, —CO₂H, —CO₂C₁-C₆alkyl,—C(═O)SC₁-C₆alkyl, —NR³R⁴, —C(═O)NR³R⁴, —NR³C(═O)OC₁-C₆ alkyl,—NR³C(═O)NR³R⁴, —S(O)_(x)C₁-C₆ alkyl, —S(O)_(y)NR³R⁴, —NR³S(O)_(y)NR³R⁴,halogen, —CN, —NO₂, and a 5-6-membered heterocyclic ring having 1-4heteroatoms independently selected from N, S, and O, said heterocyclicring optionally also comprising a carbonyl group and optionally alsocomprising 1-3 double bonds, wherein the point of attachment of saidheterocyclic ring to the attached ring is a carbon atom, wherein saidheterocyclic ring is optionally substituted with 1-5 substituent groupsindependently selected from halogen, —C₁-C₃ alkyl, and —OC₁-C₃ alkyl,wherein —C₁-C₃ alkyl and —OC₁-C₃ alkyl are optionally substituted with1-7 halogens;

wherein for compounds in which R^(a) is selected from the groupconsisting of —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₃-C₈cycloalkyl optionally having 1-3 double bonds, —C₁-C₆alkyl, —OC₂-C₆alkenyl, —OC₂-C₆ alkynyl, —OC₃-C₈ cycloalkyl optionally having 1-3double bonds, —C(═O)C₁-C₆alkyl, —C(═O)C₃-C₈ cycloalkyl, —CO₂C₁-C₆alkyl,—C(═O)SC₁-C₆alkyl, —NR³C(═O)OC₁-C₆ alkyl, and —S(O)_(x)C₁-C₆ alkyl, thenR^(a) is optionally substituted with 1-15 halogens and is optionallyalso substituted with 1-3 substituent groups independently selected from(a) —OH, (b) —CN, (c) —NR³R⁴, (d) —C₃-C₈ cycloalkyl optionally having1-3 double bonds and optionally substituted with 1-15 halogens, (e)—OC₁-C₄alkyl optionally substituted with 1-9 halogens and optionallyalso substituted with 1-2 substituent groups independently selected from—OC₁-C₂ alkyl, (f) —OC₃-C₈ cycloalkyl optionally having 1-3 double bondsand optionally substituted with 1-15 halogens, (g) —CO₂H, (h) —C(═O)CH₃,and (i) —CO₂C₁-C₄alkyl which is optionally substituted with 1-9halogens;

with the proviso that when B is A¹, and X and Y are —CH₂—, and Z is—C(═O)—, and R² is phenyl which has a substituent R^(a) in the4-position, wherein R^(a) is —OC₁-C₆alkyl which is optionallysubstituted with 1-11 halogens, then there are no other R^(a)substitutents on R² in which R^(a) is selected from —OC₁-C₆alkyl,—OC₂-C₆ alkenyl, —OC₂-C₆ alkynyl, and —OC₃-C₈ cycloalkyl optionallyhaving 1-3 double bonds, all of which are optionally substituted asdescribed above.

In many of the compounds of Formula I, Ia, Ib, Ic and Id, andpharmaceutically acceptable salts thereof,

A³ is phenyl, which is optionally substituted with 1-4 substituentgroups R^(a), wherein R^(a) is independently selected from —C₁-C₅ alkyl,—OC₁-C₃alkyl, —CO₂C₁-C₃alkyl, —CO₂H, halogen, —NR³R⁴, —C(═O)C₁-C₃alkyl,—C(═O)H, —C(═O)NR³R⁴, —SC₁-C₃ alkyl, —C₂-C₃ alkenyl, —CN, —NO₂, and1,2,4-oxadiazolyl, wherein —C₁-C₃ alkyl and —C₁-C₅ alkyl in alloccurrences is optionally substituted with 1-6 substituentsindependently selected from 1-5 halogens and one —OH group; and —C₂-C₃alkenyl is optionally substituted with 1-3 halogens.

In many of the compounds of Formula I, Ia, Ib, Ic, and Id, andpharmaceutically acceptable salts thereof,

A² is selected from the group consisting of phenyl, cyclohexyl, and aheterocyclic 5-6 membered ring comprising 1-2 heteroatoms independentlyselected from O, N, S, and —N(O)— and optionally also comprising 1-3double bonds, wherein A² is optionally substituted with 1-2 substituentgroups independently selected from —C₁-C₄ alkyl, —OC₁-C₃ alkyl, —NO₂,—CN, —S(O)_(x)C₁-C₃ alkyl, —NHS(O)₂C₁-C₃ alkyl, —NR³R⁴, —NR³C(═O)R⁴,—C₂-C₃ alkenyl, —C(═O)NR³R⁴, halogen, and pyridyl, wherein C₁-C₃ alkyl,C₁-C₄ alkyl, and C₂-C₃alkenyl in all instances is optionally substitutedwith 1-3 halogens, with the proviso that for compounds of formula Ia,when B is A¹, and X and Y are —CH₂—, and Z is —C(═O)—, and R² is phenyl,then the number of R^(a) groups on R² that are selected from—OC₁-C₃alkyl which are optionally substituted is 0 or 1.

In many of the compounds of Formula I, Ia, Ib, Ic, and Id, andpharmaceutically acceptable salts thereof, R³ and R⁴ are eachindependently selected from H and —C₁-C₃ alkyl.

In many of the compounds of Formula I, Ia, Ib, Ic, and Id, andpharmaceutically acceptable salts thereof, p is 0-2.

In subgroups of compounds of Formula I, including pharmaceuticallyacceptable salts thereof, A¹ is

Wherein R⁷ and R⁸ are each independently selected from the groupconsisting of H, halogen, —NR³R⁴, —C₁-C₃ alkyl, —OC₁-C₃ alkyl, —CN,—NO₂, and pyridyl, wherein C₁-C₃ alkyl in all instances is optionallysubstituted with 1-3 halogens.

In sub-groups of the compounds of formula I, A² is selected from thegroup consisting of phenyl, pyridyl, and cyclohexyl, wherein A² isoptionally substituted with 1-2 substituents independently selected from—C₁-C₄ alkyl, —OC₁-C₄ alkyl, —NO₂, —CN, and halogen, wherein C₁-C₄ alkylin all uses is optionally substituted with 1-3 halogens, with theproviso that for compounds of formula I, when B is A1, and X and Y areCH₂, and Z is —(C═O)—, and R² is phenyl, then the number of R^(a) groupson R² that are selected from —OC₁-C₄alkyl optionally substituted with1-3 halogens is 0 or 1.

In other subgroups, A² is optionally substituted with 1-2 substituentgroups independently selected from halogen, —C₁-C₄ alkyl, and —CN,wherein —C₁-C₄ alkyl is optionally substituted with 1-3 halogens.

In many embodiments of the invention, as described above, includingpharmaceutically acceptable salts,

A¹ is

Wherein R⁷ is selected from H, halogen, —NR³R⁴, —C₁-C₃ alkyl, —OC₁-C₃alkyl, —CN, —NO₂, and pyridyl, wherein C₁-C₃ alkyl in all instances isoptionally substituted with 1-3 halogens; and

R⁸ is selected from the group consisting of H, halogen, —CH₃, —CF₃,—OCH₃, and —OCF₃.

In many preferred embodiments of this invention, A³ is phenyl, which issubstituted with 1-3 substituents independently selected fromC₁-C₄alkyl, OC₁-C₄alkyl, —CN, Cl, F, —C(═O)CH₃, —CH═CH₂, —CO₂H, —CO₂CH₃,—S—CH₃, —S(O)CH₃, —S(O)₂CH₃, and —C(═O)NR³R⁴, wherein C₁-C₄alkyl and—OC₁-C₄alkyl are optionally substituted with 1-5 F substituents andoptionally also substituted with one group —OH.

In other embodiments, A3 is phenyl which is optionally substituted with1-3 substituents independently selected from the group consisting of Cl,F, —C₁-C₄ alkyl, and —OC₁-C₄ alkyl, wherein —C₁-C₄ alkyl and —OC₁-C₄alkyl are optionally substituted with 1-5 F.

A preferred value of Y is —(CRR¹)—.

In some embodiments, R and R⁶ are each independently selected from thegroup consisting of H and —C₁-C₅ alkyl, wherein —C₁-C₅ alkyl isoptionally substituted with 1-11 halogens. In subsets, of theseembodiments, R¹ is selected from the group consisting of H, —C₁-C₅alkyl, and —(C(R)₂)_(n)A², wherein —C₁-C₅ alkyl is optionallysubstituted with 1-11 halogens. In these, one of B and R² is A¹; and oneof B, R¹, and R² is A² or —(C(R)₂)_(n)A²; so that the compound ofFormula I comprises one group A¹ and one group A².

In subgroups of compounds, A³ is selected from the group consisting of:

-   -   (a) an aromatic ring selected from phenyl and naphthyl;    -   (b) a 5-6-membered heterocyclic ring having 1-4 heteroatoms        independently selected from N, S, O, and —N(O)—, and optionally        also comprising 1-3 double bonds and a carbonyl group, wherein        the point of attachment of A³ to the phenyl ring to which A³ is        attached is a carbon atom; and    -   (c) a benzoheterocyclic ring comprising a phenyl ring fused to a        5-6-membered heterocyclic ring having 1-2 heteroatoms        independently selected from O, N, and —S(O)_(x)— and optionally        1-2 double bonds, wherein the point of attachment of A³ to the        phenyl ring to which A³ is attached is a carbon atom.

In subgroups of compounds, A² is selected from the group consisting of:

-   -   (a) an aromatic ring selected from phenyl and naphthyl;    -   (b) a 5-6-membered heterocyclic ring having 1-4 heteroatoms        independently selected from N, S, O, and —N(O)—, and optionally        also comprising 1-3 double bonds and a carbonyl group;    -   (c) a benzoheterocyclic ring comprising a phenyl ring fused to a        5-6-membered heterocyclic ring having 1-2 heteroatoms        independently selected from O, N, and S and optionally 1-2        double bonds; and    -   (d) a —C₃-C₈ cycloalkyl ring optionally having 1-3 double bonds;

In the subgroups of A³ and A² above, A³ and A² are each optionallysubstituted with 1-4 substituent groups independently selected fromR^(a).

A subgroup of R^(a) comprises substituents that are independentlyselected from the group consisting of —C₁-C₆ alkyl, —C₂-C₆ alkenyl,—C₃-C₈ cycloalkyl optionally having 1-3 double bonds, —OC₁-C₆alkyl,—C(═O)C₁-C₆alkyl, —C(═O)H, —CO₂H, —CO₂C₁-C₆alkyl, —OH, —NR³R⁴,—NR³C(═O)OC₁-C₆ alkyl, —S(O)_(x)C₁-C₆ alkyl, halogen, —CN, —NO₂, and a5-6-membered heterocyclic ring having 1-4 heteroatoms independentlyselected from N, S, and O, said heterocyclic ring optionally alsocomprising a carbonyl group and optionally also comprising 1-3 doublebonds, wherein the point of attachment of said heterocyclic ring to thering to which R^(a) is attached is a carbon atom, wherein saidheterocyclic ring is optionally substituted with 1-5 substituent groupsindependently selected from halogen, —C₁-C₃ alkyl, and —OC₁-C₃ alkyl,wherein —C₁-C₃ alkyl and —OC₁-C₃ alkyl are optionally substituted with1-7 halogens;

wherein for compounds in which R^(a) is selected from the groupconsisting of —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₃-C₈ cycloalkyl optionallyhaving 1-3 double bonds, —OC₁-C₆alkyl, —C(═O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl,—NR³C(═O)OC₁-C₆ alkyl, and —S(O)_(x)C₁-C₆ alkyl, R^(a) is optionallysubstituted with 1-15 halogens and is optionally also substituted withone substituent group selected from (a) —OH, (b) —NR³R⁴, (c)—OC₁-C₄alkyl optionally substituted with 1-9 halogens and optionallyalso substituted with 1-2 substituent groups independently selected from—OC₁-C₂ alkyl and phenyl, and (d) phenyl which is optionally substitutedwith 1-3 groups independently selected from halogen, —CH₃, —CF₃, —OCH₃,and —OCF₃;

with the proviso that when B is A¹, and X and Y are —CH₂—, and Z is—C(═O)—, and R² is phenyl which has a substituent R^(a) in the4-position, wherein R^(a) is —OC₁-C₆alkyl which is optionallysubstituted as described above, then there are no other R^(a)substitutents on R² in which R^(a) is —OH or —OC₁-C₆alkyl which isoptionally substituted as described above.

In subgroups of compounds, n is an integer from 0-2. In other subgroups,n is 1 or 2.

In independent subgroups, R³ and R⁴ are each independently selected fromH and —C₁-C₅ alkyl, wherein —C₁-C₈ alkyl in all instances is optionallysubstituted with 1-11 halogens. In other independent subgroups, R³ andR⁴ each independently selected from H and —C₁-C₃ alkyl, or from H and—C₁-C₂ alkyl.

In subgroups of Formula I, Z is selected from the group consisting of—C(═O)—, —S(O)₂—, and —C(═N—R⁹)—, where R⁹ is selected from the groupconsisting of H, —CN, and CH₃. A preferred value of Z is —C(═O)—.

In independent subgroups, R⁵ is selected from the group consisting of H,—OH, and —C₁-C₅ alkyl, wherein —C₁-C₅ alkyl is optionally substitutedwith 1-11 halogens. In other subgroups, R⁵ is selected from H and —C₁-C₃alkyl, or from H and —C₁-C₂ alkyl.

In some subgroups, each R is independently selected from the groupconsisting of H and C₁-C₃ alkyl. In other groups, R is selected from Hand C₁-C₂ alkyl. In other groups, R is H or CH₃

In some subgroups, R⁶ is selected from the group consisting of H and—C₁-C₃ alkyl, wherein C₁-C₃ alkyl is optionally substituted with 1-5halogens. In other subgroups, R⁶ is selected from H and C₁-C₂ alkyl. Inother groups, R⁶ is H or CH₃,

In some subgroups, R¹ is selected from the group consisting of H, —C₁-C₃alkyl, and —(C(R)₂)_(n)A², wherein —C₁-C₃ alkyl is optionallysubstituted with 1-5 halogens; and R² is selected from the groupconsisting of H, —C₁-C₃ alkyl, A¹, and —(C(R)₂)_(n)A², wherein —C₁-C₃alkyl is optionally substituted with 1-5 halogens, and R⁶ is H or alkyl.In these subgroups, one of B and R² is A¹; and one of B, R¹, and R² isA² or —(C(R)₂)_(n)A²; so that the compound of Formula I comprises onegroup A¹ and one group A².

In subgroups of compounds, A³ is selected from the group consisting of:

-   -   (a) phenyl;    -   (b) a 5-6-membered aromatic heterocyclic ring having 1-2        heteroatoms independently selected from N, S, O, and —N(O)—,        wherein the point of attachment of A³ to the phenyl ring to        which A³ is attached is a carbon atom; and    -   (c) a benzoheterocyclic ring comprising a phenyl ring fused to a        5-membered aromatic heterocyclic ring having 1-2 heteroatoms        independently selected from O, N, and —S(O)_(x), wherein the        point of attachment of A³ to the phenyl ring to which A³ is        attached is a carbon atom.

In subgroups, A² is selected from:

-   -   (a) phenyl;    -   (b) a 5-6-membered heterocyclic ring having 1-4 heteroatoms        independently selected from N, S, O, and —N(O)—, and optionally        also comprising 1-3 double bonds;    -   (c) a benzoheterocyclic ring comprising a phenyl ring fused to a        5-membered heterocyclic ring having 1-2 heteroatoms        independently selected from O, N, and S; and    -   (d) a —C₅-C₆ cycloalkyl ring.

In many compounds, A³ and A² are each optionally substituted with 1-4substituent groups independently selected from R^(a). In varioussubgroups, A³ is optionally substituted with 1-3 substituents R^(a), orwith 2-3 substituents R^(a). In various subgroups, A² is optionallysubstituted with 1-3 substituents R^(a), or with 1-2 substituents R^(a).Often A² is substituted with 2 substituents R^(a), or with 2-3substituents R^(a).

In many compounds, A³ is selected from the group consisting of phenyl,thienyl, imidazolyl, pyrrolyl, pyrazolyl, pyridyl, N-oxido-pyridyl,thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzothienyl,benzothienyl-5-oxide, and benzothienyl-5-dioxide.

In many compounds, A² is selected from the group consisting of phenyl,thienyl, imidazolyl, thiazolyl, pyrrolyl, pyrazolyl, 1,2,4-triazolyl,tetrazolyl, benzodioxolyl, pyridyl, N-oxido-pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, cyclopentyl, cyclohexyl, and tetrahydropyranyl.

In some subsets, R^(a) is selected from the group consisting of —C₁-C₄alkyl, —C₂-C₄ alkenyl, cyclopropyl, —OC₁-C₂alkyl, —C(═O)C₁-C₂alkyl,—C(═O)H, —CO₂C₁-C₄alkyl, —OH, —NR³R⁴, —NR³C(═O)OC₁-C₄ alkyl,—S(O)_(x)C₁-C₂ alkyl, halogen, —CN, —NO₂, and a 5-6-memberedheterocyclic ring having 1-2 heteroatoms independently selected from N,S, and O, wherein the point of attachment of said heterocyclic ring tothe ring to which R^(a) is attached ring is a carbon atom, wherein saidheterocyclic ring is optionally substituted with 1-5 substituent groupsindependently selected from halogen;

wherein for compounds in which R^(a) is selected from the groupconsisting of —C₁-C₄ alkyl, —C₂-C₄ alkenyl, —OC₁-C₂alkyl,—C(═O)C₁-C₂alkyl, —CO₂C₁-C₄alkyl, —NR³C(═O)OC₁-C₄ alkyl, and—S(O)_(x)C₁-C₂ alkyl, the alkyl group of R^(a) is optionally substitutedwith 1-5 halogens and is optionally also substituted with onesubstituent group selected from (a) —OH, (b) —NR³R⁴, (c) —OCH₃optionally substituted with 1-3 fluorine atoms and optionally alsosubstituted with one phenyl group, and (d) phenyl which is optionallysubstituted with 1-3 groups independently selected from halogen, —CH₃,—CF₃, —OCH₃, and —OCF₃;

with the proviso that when B is A¹, and X and Y are —CH₂—, and Z is—C(═O)—, and R² is phenyl which has a substituent R^(a) in the4-position, wherein R^(a) is —OC₁-C₂alkyl which is optionallysubstituted as described above, then there are no other R^(a)substitutents on R² in which R^(a) is selected from —OH or —OC₁-C₂alkylwhich is optionally substituted as described above.

In preferred subsets, X is selected from the group consisting of —O—,—NH—, and —N(C₁-C₃alkyl)-. X may also be selected from the groupconsisting of —O—, —NH—, and —N(CH₃). In highly preferred subsets, X isO.

In many subsets, Z is —C(═O)—.

A preferred subgroup of compounds has Formula Ie, includingpharmaceutically acceptable salts thereof

In compounds of formula Ie, X is selected from the group consisting of—O—, —NH—, —N(C₁-C₅alkyl)- and —(CH₂)—;

Z is selected from the group consisting of —C(═O)—, —S(O)₂—, and—C(═N—R⁹)—, wherein R⁹ is selected from the group consisting of H, —CN,and C₁-C₅alkyl optionally substituted with 1-11 halogens;

Each R is independently selected from the group consisting of H and—CH₃;

B is selected from the group consisting of A¹ and A², wherein A¹ has thestructure:

R¹ is selected from the group consisting of H, —C₁-C₅ alkyl, and—(C(R)₂)_(n)A², wherein —C₁-C₅ alkyl is optionally substituted with 1-11halogens;

R² is selected from the group consisting of H, —C₁-C₅ alkyl, A¹, and—(C(R)₂)_(n)A², wherein —C₁-C₅alkyl is optionally substituted with 1-11halogens;

Wherein one of B and R² is A¹; and one of B, R¹, and R² is A² or—(C(R)₂)_(n)A²; so that the compound of Formula Ie comprises one groupA¹ and one group A²;

A² is selected from the group consisting of phenyl, cyclohexyl, andpyridyl, wherein A² is optionally substituted with 1-2 substituentgroups independently selected from halogen, —C₁-C₄ alkyl, and —CN,wherein —C₁-C₄ alkyl is optionally substituted with 1-3 halogens;

Each R^(a) is independently selected from the group consisting of —C₁-C₃alkyl and halogen, wherein —C₁-C₃ alkyl is optionally substituted with1-3 halogens;

Each R^(b) is independently selected from the group consisting of Cl, F,—C₁-C₄ alkyl, and —OC₁-C₄ alkyl, wherein —C₁-C₄ alkyl and —OC₁-C₄ alkylare optionally substituted with 1-5 F;

n is 0 or 1;

p is an integer from 0-2; and

q is an integer from 0-3.

Subsets of compounds having formula Ie include compounds of formula If,Ig, and Ih, and pharmaceutically acceptable salts thereof:

In the compounds of formula If, Ig, and Ih, R¹ and R² are eachindependently selected from H and —C₁-C₅ alkyl, wherein —C₁-C₅ alkyl isoptionally substituted with 1-11 halogens. Other groups are as definedpreviously.

In subsets of the compounds described above, A² may be selected from thegroup consisting of phenyl, cyclohexyl, and pyridyl, wherein A² isoptionally substituted with 1-2 substituent groups independentlyselected from halogen, —CH₃—CF₃, and —CN.

In subsets of the compounds described above, each R^(a) independently isselected from the group consisting of —CF₃ and Cl.

In subsets of the compounds described above, each R^(b) is independentlyselected from the group consisting of —C₁-C₃ alkyl, —OCH₃, and F.

In subsets of the compounds described above, R¹ and R² are eachindependently selected from the group consisting of H and —C₁-C₂ alkyl.

In subsets of the compounds described above, X is selected from —O—,—NH—, —N(CH₃)—, and —CH₂—.

In subsets of the compounds described above, Z is selected from thegroup consisting of —C(═O)—, —S(O)₂—, and —C(═N—CN)—.

In subsets of the compounds described above, p is 1.

In subsets of the compounds described above, q is 2 or 3.

A subset of compounds defined previously comprises compounds havingformula II, and pharmaceutically acceptable salts thereof:

In formula Ii, R⁷ is selected from the group consisting of Cl and —CF₃;

R^(c) is selected from the group consisting of halogen, —CH₃—CF₃ and—CN; and

t is an integer from 0-2. Other groups are as defined previously.

A subset of compounds defined previously comprises compounds havingformula Ij, or a pharmaceutically acceptable salt thereof:

In formula Ii, R⁷ is selected from the group consisting of Cl and —CF₃

R^(c) is selected from the group consisting of halogen, —CH₃—CF₃, and—CN; and

t is an integer from 0-2. Other groups are as defined previously.

DEFINITIONS

“Ac” is acetyl, which is CH₃C(═O)—.

“Alkyl” means saturated carbon chains which may be linear or branched orcombinations thereof, unless the carbon chain is defined otherwise.Other groups having the prefix “alk”, such as alkoxy and alkanoyl, alsomay be linear or branched or combinations thereof, unless the carbonchain is defined otherwise. Examples of alkyl groups include methyl,ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl,heptyl, octyl, nonyl, and the like.

“Alkylene” groups are alkyl groups that are difunctional rather thanmonofunctional. For example, methyl is an alkyl group and methylene(—CH₂—) is the corresponding alkylene group.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched or combinationsthereof. Examples of alkenyl include vinyl, alkyl, isopropenyl,pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl,and the like.

“Alkynyl” means carbon chains which contain at least one carbon-carbontriple bond, and which may be linear or branched or combinationsthereof. Examples of alkynyl include ethynyl, propargyl,3-methyl-1-pentynyl, 2-heptynyl and the like.

“Cycloalkyl” means a saturated carbocyclic ring having from 3 to 8carbon atoms, unless otherwise stated (e.g., cycloalkyl may be definedas having one or more double bonds). The term also includes a cycloalkylring fused to an aryl group. Examples of cycloalkyl include cyclopropyl,cyclopentyl, cyclohexyl, cycloheptyl, and the like. “Cycloalkenyl” meansa non-aromatic carbocyclic ring having one or more double binds.

“Aryl” (and “arylene”) when used to describe a substituent or group in astructure means a monocyclic or bicyclic compound in which the rings arearomatic and which contains only carbon ring atoms. The term “aryl” canalso refer to an aryl group that is fused to a cycloalkyl orheterocycle. Preferred “aryls” are phenyl and naphthyl. Phenyl isgenerally the most preferred aryl group.

“EDC” is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

“Heterocyclyl,” “heterocycle,” and “heterocyclic” means a fully orpartially saturated or aromatic 5-6 membered ring containing 1-4heteroatoms independently selected from N, S and O, unless otherwisestated.

“Benzoheterocycle” represents a phenyl ring fused to a 5-6-memberedheterocyclic ring having 1-2 heteroatoms, each of which is O, N, or S,where the heterocyclic ring may be saturated or unsaturated. Examplesinclude indole, benzofuran, 2,3-dihydrobenzofuran and quinoline.

“DIPEA” is diisopropylethylamine.

“Halogen” includes fluorine, chlorine, bromine and iodine.

“HOBT” is 1-Hydroxybenzotriazole.

“IPAC” is isopropyl acetate.

“Me” represents methyl.

“Weinreb amine” is N,O-dimethylhydroxylamine.

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

The substituent “tetrazole” means a 2H-tetrazol-5-yl substituent groupand tautomers thereof.

Optical Isomers—Diastereomers—Geometric Isomers—Tautomers

Compounds of Formula I may contain one or more asymmetric centers andcan thus occur as racemates, racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to include all such isomeric forms of the compoundsof Formula I and all mixtures of the compounds. When structures areshown with a stereochemical representation, other stereochemicalstructures are also included individually and collectively, such asenantiomers, diastereoisomers (where diastereomers are possible), andmixtures of the enantiomers and/or diastereomers, including racemicmixtures.

Some of the compounds described herein may contain olefinic doublebonds, and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist as tautomers. Anexample is a ketone and its enol form, known as keto-enol tautomers. Theindividual tautomers as well as mixtures thereof are encompassed withcompounds of Formula I.

Compounds of Formula I having one or more asymmetric centers may beseparated into diastereoisomers, enantiomers, and the like by methodswell known in the art.

Alternatively, enantiomers and other compounds with chiral centers maybe synthesized by stereospecific synthesis using optically pure startingmaterials and/or reagents of known configuration.

Some of the biphenyl and biaryl compounds herein are observed asmixtures of atropisomers (rotamers) in the NMR spectra. The individualatropisomers as well as mixtures thereof are encompassed with thecompounds of this invention.

Salts

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, magnesium, potassium, and sodium salts. Salts in thesolid form may exist in more than one crystal structure, and may also bein the form of hydrates. Salts derived from pharmaceutically acceptableorganic non-toxic bases include salts of primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids.

It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Metabolites—Prodrugs

Therapeutically active metabolites, where the metabolites themselvesfall within the scope of the claimed invention, are also compounds ofthe current invention. Prodrugs, which are compounds that are convertedto the claimed compounds as they are being administered to a patient orafter they have been administered to a patient, are also compounds ofthis invention.

Utilities

Compounds of the current invention are potent inhibitors of CETP. Theyare therefore useful in treating diseases and conditions that aretreated by inhibitors of CETP.

One aspect of the present invention provides a method for treating orreducing the risk of developing a disease or condition that may betreated or prevented by inhibition of CETP by administering atherapeutically effective amount of a compound of this invention to apatient in need of treatment. A patient is a human or mammal, and ismost often a human. A “therapeutically effective amount” is the amountof compound that is effective in obtaining a desired clinical outcome inthe treatment of a specific disease.

Diseases or conditions that may be treated with compounds of thisinvention, or which the patient may have a reduced risk of developing asa result of being treated with the compounds of this invention, include:atherosclerosis, peripheral vascular disease, dyslipidemia,hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia,familial-hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity, endotoxemia, and metabolic syndrome.

The compounds of this invention are expected to be particularlyeffective in raising HDL-C and/or increasing the ratio of HDL-C toLDL-C. These changes in HDL-C and LDL-C may be beneficial in treatingatherosclerosis, reducing or reversing the development ofatherosclerosis, reducing the risk of developing atherosclerosis, orpreventing atherosclerosis.

Administration and Dose Ranges

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like. Preferably compounds ofFormula I are administered orally.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

When treating the diseases for which compounds of Formula I areindicated, generally satisfactory results are obtained when thecompounds of the present invention are administered at a daily dosage offrom about 0.01 milligram to about 100 milligram per kilogram of animalor human body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Inthe case of a 70 kg adult human, the total daily dose will generally befrom about 0.5 milligram to about 500 milligrams. For a particularlypotent compound, the dosage for an adult human may be as low as 0.1 mg.The dosage regimen may be adjusted within this range or even outside ofthis range to provide the optimal therapeutic response.

Oral administration will usually be carried out using tablets. Examplesof doses in tablets are 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg,100 mg, 250 mg, and 500 mg. Other oral forms can also have the samedosages (e.g. capsules).

Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceuticalcompositions which comprise a compound of Formula I and apharmaceutically acceptable carrier. The pharmaceutical compositions ofthe present invention comprise a compound of Formula I or apharmaceutically acceptable salt as an active ingredient, as well as apharmaceutically acceptable carrier and optionally other therapeuticingredients. The term “pharmaceutically acceptable salts” refers tosalts prepared from pharmaceutically acceptable non-toxic bases or acidsincluding inorganic bases or acids and organic bases or acids. Apharmaceutical composition may also comprise a prodrug, or apharmaceutically acceptable salt thereof, if a prodrug is administered.Pharmaceutical compositions may also consist essentially of a compoundof Formula I and a pharmaceutically acceptable carrier without othertherapeutic ingredients.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, hard and soft capsules and tablets, with the solidoral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe coated by standard aqueous or nonaqueous techniques. Suchcompositions and preparations should contain at least 0.1 percent ofactive compound. The percentage of active compound in these compositionsmay, of course, be varied and may conveniently be between about 2percent to about 60 percent of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage will be obtained. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Compounds of formula I may also be administered parenterally. Solutionsor suspensions of these active compounds can be prepared in watersuitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Combination Therapy

Compounds of the invention (e.g. Formula I and Ia-Ij) may be used incombination with other drugs that may also be useful in the treatment oramelioration of the diseases or conditions for which compounds ofFormula I are useful. Such other drugs may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of Formula I. When a compound of Formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of Formula I is preferred. However, the combination therapyalso includes therapies in which the compound of Formula I and one ormore other drugs are administered on different schedules.

When oral formulations are used, the drugs may be combined into a singlecombination tablet or other oral dosage form, or the drugs may bepackaged together as separate tablets or other oral dosage forms. It isalso contemplated that when used in combination with one or more otheractive ingredients, the compound of the present invention and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of Formula I.

Examples of other active ingredients that may be administered incombination with a compound of this invention (e.g. Formula I), andeither administered separately or in the same pharmaceuticalcomposition, include, but are not limited to, other compounds whichimprove a patient's lipid profile, such as (i) HMG-CoA reductaseinhibitors, (which are generally statins, including lovastatin,simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin,rivastatin, itavastatin, pitavastatin, and other statins), (ii) bileacid sequestrants (cholestyramine, colestipol, dialkylaminoalkylderivatives of a cross-linked dextran, Colestid®, LoCholest®, (iii)niacin and related compounds, such as nicotinyl alcohol, nicotinamide,and nicotinic acid or a salt thereof, (iv) PPARα agonists, such asgemfibrozil and fenofibric acid derivatives (fibrates), includingclofibrate, fenofibrate, bezafibrate, ciprofibrate, and etofibrate, (v)cholesterol absorption inhibitors, such as stanol esters,beta-sitosterol, sterol glycosides such as tiqueside; and azetidinones,such as ezetimibe, (vi) acyl CoA:cholesterol acyltransferase (ACAT)inhibitors, such as avasimibe and melinamide, and including selectiveACAT-1 and ACAT-2 inhibitors and dual inhibitors, (vii) phenolicanti-oxidants, such as probucol, (viii) microsomal triglyceride transferprotein (MTP)/ApoB secretion inhibitors, (ix) anti-oxidant vitamins,such as vitamins C and E and beta carotene, (x) thyromimetics, (xi) LDL(low density lipoprotein) receptor inducers, (xii) platelet aggregationinhibitors, for example glycoprotein IIb/IIIa fibrinogen receptorantagonists and aspirin, (xiii) vitamin B12 (also known ascyanocobalamin), (xiv) folic acid or a pharmaceutically acceptable saltor ester thereof, such as the sodium salt and the methylglucamine salt,(xv) FXR and LXR ligands, including both inhibitors and agonists, (xvi)agents that enhance ABCA1 gene expression, and (xvii) ileal bile acidtransporters.

Preferred classes of therapeutic compounds that can be used with thecompounds of this invention for use in improving a patient's lipidprofile (i.e. raising HDL-C and lowering LDL-C) include one or both ofstatins and cholesterol absorption inhibitors. Particularly preferredare combinations of compounds of this invention with simvastatin,ezetimibe, or both simvastatin and ezetimibe. Also preferred arecombinations of compounds of this invention with statins other thansimvastatin, such as lovastatin, rosuvastatin, pravastatin, fluvastatin,atorvastatin, rivastatin, itavastatin, and ZD-4522.

Finally compounds of this invention can be used with compounds that areuseful for treating other diseases, such as diabetes, hypertension andobesity, as well as other anti-atherosclerotic compounds. Suchcombinations may be used to treat one or more of such diseases asdiabetes, obesity, atherosclerosis, and dyslipidemia, or more than oneof the diseases associated with metabolic syndrome. The combinations mayexhibit synergistic activity in treating these disease, allowing for thepossibility of administering reduced doses of active ingredients, suchas doses that otherwise might be sub-therapeutic.

Examples of other active ingredients that may be administered incombination with a compound of this invention include, but are notlimited to, compounds that are primarily anti-diabetic compounds,including:

(a) PPAR gamma agonists and partial agonists, including glitazones andnon-glitazones (e.g. pioglitazone, englitazone, MCC-555, rosiglitazone,balaglitazone, netoglitazone, T-131, LY-300512, and LY-818;

(b) biguanides such as metformin and phenformin;

(c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;

(d) dipeptidyl peptidase IV (DP-IV) inhibitors, including vildagliptin,sitagliptin, and saxagliptin;

(e) insulin or insulin mimetics, such as for example insulin lispro,insulin glargine, insulin zinc suspension, and inhaled insulinformulations;

(f) sulfonylureas, such as tolbutamide, glipizide, glimepiride,acetohexamide, chlorpropamide, glibenclamide, and related materials;

(g) α-glucosidase inhibitors (such as acarbose, adiposine; camiglibose;emiglitate; miglitol; voglibose; pradimicin-Q; and salbostatin);

(h) PPARα/γ dual agonists, such as muraglitazar, tesaglitazar,farglitazar, and naveglitazar;

(i) PPARδ agonists such as GW501516 and those disclosed in WO97/28149;

(j) glucagon receptor antagonists;

(k) GLP-1; GLP-1 derivatives; GLP-1 analogs, such as exendins, such asfor example exenatide (Byetta); and non-peptidyl GLP-1 receptoragonists;

(l) GIP-1; and

(m) Non-sulfonylurea insulin secretagogues, such as the meglitinides(e.g. nateglinide and rapeglinide).

These other active ingredients that may be used in combination with thecurrent invention also include antiobesity compounds, including5-HT(serotonin) inhibitors, neuropeptide Y5 (NPY5) inhibitors,melanocortin 4 receptor (Mc4r) agonists, cannabinoid receptor 1 (CB-1)antagonists/inverse agonists, and β₃ adrenergic receptor agonists. Theseare listed in more detail later in this section.

These other active ingredients also include active ingredients that areused to treat inflammatory conditions, such as aspirin, non-steroidalanti-inflammatory drugs, glucocorticoids, azulfidine, and selectivecyclooxygenase-2 (COX-2) inhibitors, including etoricoxib, celecoxib,rofecoxib, and Bextra.

Antihypertensive compounds may also be used advantageously incombination therapy with the compounds of this invention. Examples ofantihypertensive compounds that may be used with the compounds of thisinvention include (1) angiotensin II antagonists, such as losartan; (2)angiotensin converting enzyme inhibitors (ACE inhibitors), such asenalapril and captopril; (3) calcium channel blockers such as nifedipineand diltiazem; and (4) endothelian antagonists.

Anti-obesity compounds may be administered in combination with thecompounds of this invention, including: (1) growth hormone secretagoguesand growth hormone secretagogue receptor agonists/antagonists, such asNN703, hexarelin, and MK-0677; (2) protein tyrosine phosphatase-1B(PTP-1B) inhibitors; (3) cannabinoid receptor ligands, such ascannabinoid CB₁ receptor antagonists or inverse agonists, such asrimonabant (Sanofi Synthelabo), AMT-251, and SR-14778 and SR 141716A(Sanofi Synthelabo), SLV-319 (Solvay), BAY 65-2520 (Bayer); (4)anti-obesity serotonergic agents, such as fenfluramine, dexfenfluramine,phentermine, and sibutramine; (5) β3-adrenoreceptor agonists, such asAD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344,L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, Trecadrine, ZenecaD7114, and SR 59119A; (6) pancreatic lipase inhibitors, such as orlistat(Xenical®), Triton WR1339, RHC80267, lipstatin, tetrahydrolipstatin,teasaponin, and diethylumbelliferyl phosphate; (7) neuropeptide Y1antagonists, such as BIBP3226, J-115814, BIBO 3304, LY-357897,CP-671906, and GI-264879A; (8) neuropeptide Y5 antagonists, such asGW-569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662,FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170,SR-120562A, SR-120819A and JCF-104; (9) melanin-concentrating hormone(MCH) receptor antagonists; (10) melanin-concentrating hormone 1receptor (MCH1R) antagonists, such as T-226296 (Takeda); (11)melanin-concentrating hormone 2 receptor (MCH2R) agonist/antagonists;(12) orexin-1 receptor antagonists, such as SB-334867-A; (13)melanocortin agonists, such as Melanotan II; (14) other Mc4r(melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron),ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14(Palatin); (15) 5HT-2 agonists; (16) 5HT2C (serotonin receptor 2C)agonists, such as BVT933, DPCA37215, WAY161503, and R-1065; (17) galaninantagonists; (18) CCK agonists; (19) CCK-A (cholecystokinin-A) agonists,such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 and SR146131;(20) GLP-1 agonists; (21) corticotropin-releasing hormone agonists; (22)histamine receptor-3 (H3) modulators; (23) histamine receptor-3 (H3)antagonists/inverse agonists, such as hioperamide,3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit,iodophenpropit, imoproxifan, and GT2394 (Gliatech); (24) β-hydroxysteroid dehydrogenase-1 inhibitors (11β-HSD-1 inhibitors), such as BVT3498 and, BVT 2733, (25) PDE (phosphodiesterase) inhibitors, such astheophylline, pentoxifylline, zaprinast, sildenafil, aminone, milrinone,cilostamide, rolipram, and cilomilast; (26) phosphodiesterase-3B (PDE3B)inhibitors; (27) NE (norepinephrine) transport inhibitors, such as GW320659, desipramine, talsupram, and nomifensine; (28) ghrelin receptorantagonists; (29) leptin, including recombinant human leptin (PEG-OB,Hoffman La Roche) and recombinant methionyl human leptin (Amgen); (30)leptin derivatives; (31) BRS3 (bombesin receptor subtype 3) agonistssuch as [D-Phe6, beta-Ala11, Phe13, Nle14]Bn(6-14) and [D-Phe6,Phe13]Bn(6-13) propylamide; (32) CNTF (Ciliary neurotrophic factors),such as GI-181771 (Glaxo-SmithKline), SR146131 (Sanofi Synthelabo),butabindide, PD170,292, and PD 149164 (Pfizer); (33) CNTF derivatives,such as axokine (Regeneron); (34) monoamine reuptake inhibitors, such assibutramine; (35) UCP-1 (uncoupling protein-1, 2, or 3) activators, suchas phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), and retinoic acid; (36) thyroid hormone β agonists, suchas KB-2611 (KaroBioBMS); (37) FAS (fatty acid synthase) inhibitors, suchas Cerulenin and C₇₅; (38) DGAT1 (diacylglycerol acyltransferase 1)inhibitors; (39) DGAT2 (diacylglycerol acyltransferase 2) inhibitors;(40) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (41) glucocorticoidantagonists; (42) acyl-estrogens, such as oleoyl-estrone; (43)dicarboxylate transporter inhibitors; (44) peptide YY, PYY 3-36, peptideYY analogs, derivatives, and fragments such as BIM-43073D, BIM-43004C,(45) Neuropeptide Y2 (NPY2) receptor agonists such NPY3-36, N acetyl[Leu(28,31)] NPY 24-36, TASP-V, andcyclo-(28/32)-Ac-[Lys28-G1u32]-(25-36)-pNPY; (46) Neuropeptide Y4 (NPY4)agonists such as pancreatic peptide (PP); (47) Neuropeptide Y1 (NPY1)antagonists such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906,and GI-264879A; (48) Opioid antagonists, such as nalmefene (Revex®),3-methoxynaltrexone, naloxone, and naltrexone; (49) glucose transporterinhibitors; (50) phosphate transporter inhibitors; (51) 5-HT (serotonin)inhibitors; (52) beta-blockers; (53) Neurokinin-1 receptor antagonists(NK-1 antagonists); (54) clobenzorex; (55) cloforex; (56) clominorex;(57) clortermine; (58) cyclexedrine; (59) dextroamphetamine; (60)diphemethoxidine, (61) N-ethylamphetamine; (62) fenbutrazate; (63)fenisorex; (64) fenproporex; (65) fludorex; (66) fluminorex; (67)furfurylmethylamphetamine; (68) levamfetamine; (69) levophacetoperane;(70) mefenorex; (71) metamfepramone; (72) methamphetamine; (73)norpseudoephedrine; (74) pentorex; (75) phendimetrazine; (76)phenmetrazine; (77) picilorex; (78) phytopharm 57; (79) zonisamide, (80)aminorex; (81) amphechloral; (82) amphetamine; (83) benzphetamine; and(84) chlorphentermine.

The combination therapies described above which use the compounds ofthis invention may also be useful in the treatment of the metabolicsyndrome. According to one widely used definition, a patient havingmetabolic syndrome is characterized as having three or more symptomsselected from the following group of five symptoms: (1) abdominalobesity; (2) hypertriglyceridemia; (3) low high-density lipoproteincholesterol (HDL); (4) high blood pressure; and (5) elevated fastingglucose, which may be in the range characteristic of Type 2 diabetes ifthe patient is also diabetic. Each of these symptoms is definedclinically in the recently released Third Report of the NationalCholesterol Education Program Expert Panel on Detection, Evaluation andTreatment of High Blood Cholesterol in Adults (Adult Treatment PanelIII, or ATP III), National Institutes of Health, 2001, NIH PublicationNo. 01-3670. Patients with metabolic syndrome have an increased risk ofdeveloping the macrovascular and microvascular complications that arelisted above, including atherosclerosis and coronary heart disease. Thecombinations described above may ameliorate more than one symptom ofmetabolic syndrome concurrently (e.g. two symptoms, three symptoms, foursymptoms, or all five of the symptoms).

CETP Assay

An in vitro continuous assay for determining IC₅₀'s to identifycompounds that are CETP inhibitors was performed based on a modificationof the method described by Epps et al. employing BODIPY®-CE as thecholesteryl ester lipid donor. See Epps et al. (1995) Method formeasuring the activities of cholesteryl ester transfer protein (lipidtransfer protein), Chem. Phys. Lipids. 77, 51-63.

Particles used in the assay were created from the following sources:Synthetic donor HDL particles containing DOPC (Dioleoyl PhosphatidylCholine), BODIPY®-CE (Molecular Probes C-3927), triolein (atriglyceride), and apoHDL were essentially created by probe sonicationas described by Epps et al, but with the addition of a non-diffusiblequencher molecule, dabcyl dicetylamide, in order to reduce backgroundfluorescence. Dabcyl dicetylamide was made by heating dabcyln-succinimide with dicetylamine in DMF at 95° C. overnight in thepresence of diisopropylamine catalyst. Native lipoproteins from humanblood were used as acceptor particles. Particles having a density lessthan 1.063 g/ml were collected by ultracentrifugation. These particlesinclude VLDL, IDL, and LDL. Particle concentrations were expressed interms of protein concentration as determined by BCA assay (Pierce, USA).Particles were stored at 4° C. until use.

Assays were performed in Dynex Microfluor 2 U-bottom black 96-wellplates (Cat #7205). An assay cocktail containing CETP, 1×CETP buffer (50mM Tris, pH 7.4, 100 mM NaCl, 1 mM EDTA), and half the finalconcentration of acceptor particles was prepared, and 100 μL of theassay cocktail was added to each well of the plate. Test compounds inDMSO were added in a volume of 3 μL. The plate was mixed on a plateshaker and then incubated at 25° C. for 1 hour. A second assay cocktailcontaining donor particles, the remaining acceptor particles and 1×CETPbuffer was prepared. 47 μL of the second assay cocktail was added to thereaction wells to start the assay. Assays were performed at 25° C. in afinal volume of 150 L. Final concentrations of materials were: 5 ng/mLdonor particles, 30 ng/μL acceptor particles (each expressed by proteincontent), 1×CETP buffer, 0.8 nM recombinant human CETP (expressed in CHOcells and partially purified), and up to 2% DMSO when testing compounds.The assay was followed in a fluorescence plate reader (Molecular DevicesSpectramax GeminiXS) set for a 45 minute kinetic run at 25° C. whichread the samples every 45 sec at Ex=480 nm, Em=511 nm, with a cutofffilter at 495 nm, photomultiplier tube setting of medium, calibrationon, and 6 reads/well.

Data was evaluated by obtaining an initial rate, expressed in relativefluorescence units per second, for the pseudolinear portion of thecurve, often 0-500 or 1000 sec. Comparison of the rates of samples withinhibitors to an uninhibited (DMSO only) positive control yielded apercent inhibition. A plot of percent inhibition vs. log of inhibitorconcentration, fit to a Sigmoidal 4 parameter equation was used tocalculate 1050.

EXAMPLES

The following schemes and examples are provided so that the inventionwill be more fully appreciated and understood. Starting materials aremade using known procedures or as shown below.

The examples should not be construed as limiting the invention in anyway. The scope of the invention is defined by the appended claims.Compounds of this invention have an IC₅₀ value as measured using theassay described above of less than or equal to 50 μM.

Intermediates 1-2, 1-3, 1-4, 1-5 and 1-6 utilized in the presentinvention can be purchased or prepared as shown in Scheme 1. Anappropriately substituted 2-haloaniline 1-1 wherein R^(a) and p are asdefined in the claims and where the halogen is preferably iodo or bromois treated with CuCN in DMF at elevated temperature to afford thecorresponding 2-cyanoaniline. Alternatively, the nitrile can be preparedby treatment of 1-1 with KCN and CuI in the presence of a palladium (II)salt or in the presence of certain copper or nickel complexes (See:Smith, M. B. and March, J. “March's Advanced Organic Chemistry”, 5^(th)Ed., John Wiley and Sons, New York, pp. 867 (2001) and referencestherein). Iodides 1-3 are prepared by treatment of 1-2 withisoamylnitrite, n-pentylnitrite, t-butyl nitrite or the like in thepresence of diiodomethane (see for example: Smith et al., J. Org. Chem.55, 2543, (1990) and references cited therein) either neat or in asolvent such as THF or acetonitrile. Alternatively, the iodide can beprepared first by diazonium formation using isoamylnitrite,n-pentylnitrite, t-butyl nitrite, sodium nitrite, nitrous acid or thelike followed by heating in the presence of iodine or an iodide saltsuch as copper iodide, sodium iodide, potassium iodide,tetrabutylammonium iodide or the like. Reduction of 1-3 with DIBAL indichloromethane affords aldehyde 1-4. Reduction of aldehyde 1-4 withsodium borohydride or the like in methanol or ethanol or the like givesalcohol 1-5. Treatment of 1-5 with carbon tetrabromide andtriphenylphosphine in solvents such as dichloromethane, dichloroethaneor the like gives benzyl bromide 1-6 (See: Smith, M. B. and March, J.“March's Advanced Organic Chemistry”, 5^(th) Ed., John Wiley and Sons,New York, pp. 518-519 (2001) and references therein).

Intermediates 2-2 and 2-3 of the present invention wherein R^(a), p, andA³ are as defined in the claims can be prepared as shown in Scheme 2.2-Cyanoiodobenzenes 2-1 can be purchased or prepared according to theprocedures outlined in Scheme 1. Compounds 2-2 are prepared via a Suzukior Stille reaction or variation thereof employing palladium catalyzedcross coupling of iodide 2-1 with an appropriately substituted aryl- orheteroaryl-boronic acid, -boronate ester or -trialkyl tin as describedin Miyaua et al., Chem. Rev. 95, 2457 (1995) and references cited withinand as described in Smith, M. B. and March, J. “March's Advanced OrganicChemistry”, 5^(th) Ed., John Wiley and Sons, New York, pp. 868-869(2001) and references cited therein. Reduction of nitrile 2-2 isaccomplished with lithium aluminum hydride in diethyl ether to afford2-aminomethyl aniline 2-3. Alternatively, the nitrile can be reducedwith palladium on carbon or Raney nickel under hydrogen atmosphere inmethanol, ethanol or the like. Other methods for reduction of a nitrileto an aminomethyl group can be found in Smith, M. B. and March, J.“March's Advanced Organic Chemistry”, 5^(th) Ed., John Wiley and Sons,New York, pp. 1204 (2001) and references therein.

Compounds 3-4 of the present invention wherein R, R^(a), p, A², A³ and nare as defined in the claims can be prepared according to the procedureoutlined in Scheme 3. Benzyl amines 3-1 can be purchased or preparedaccording to the procedure outlined in Scheme 2. Reaction of 3-1 with anappropriately substituted alkyl acetate bearing a leaving group at the2-position affords secondary amine 3-2. Alkyl acetates can be purchasedor prepared using known methods. The preferred leaving group is bromideor iodide, but may also be mesylate, tosylate or the like and thesolvent may be dichloromethane, dichloroethane, tetrahydrofuran,dimethoxyethane, or the like. The reaction may be run with or without abase such as triethylamine, diisopropylethylamine, N-methylmorpholine,or the like. Reduction of the ester functionality of 3-2 affords aminoalcohol 3-3. The preferred reducing reagent is LiAlH₄, in a solvent suchas ether, tetrahydrofuran, dimethoxyethane, dioxane, or the like. Othermethods for reduction of an ester can be found in “March's AdvancedOrganic Chemistry” 5^(th) Ed., John Wiley and Sons, New York, pp 1551.Amino alcohol 3-3 can be cyclised to oxazolidinone 3-4 using phosgene(Y═Cl) or a phosgene equivalent such as triphosgene (Y═OCCl₃) orcarbonyl-diimidazole (Y=imidazole) or the like in a solvent such asdichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, orthe like and a base such as triethylamine, diisopropylethylamine,N-methylmorpholine, or the like. Enantiopure products may be obtainedvia chiral chromotography.

Compounds of the present invention 4-3 wherein R, R^(a), p, A², A³ and nare as defined in the claims can be prepared as shown in Scheme 4. Anappropriately substituted benzylamine 4-1 can be reacted with anappropriately substituted oxirane to give amino alcohol 4-2. Theoxiranes may be purchased or prepared from the corresponding aldehydeand a sulfur ylide as described in “March's Advanced Organic Chemistry”5^(th) Ed., John Wiley and Sons, New York, pp 1247. Alternatively theepoxide may be made from epoxidation of an olefin, cyclization of ahalohydrin or 1,2-diol, or other methods described in “March's AdvancedOrganic Chemistry” 5^(th) Ed., John Wiley and Sons, New York, pp 1051.The preferred solvent for this reaction is isopropanol. Alternatively,the epoxide opening may be carried out in a solvent such as acetonitrileor the like with the aid of a Lewis Acid catalyst such as Yb(OTf)₃ orthe like. Amino alcohol 4-2 can be cyclised to oxazolidinone 4-3 usingphosgene (Y═Cl) or a phosgene equivalent such as triphosgene (Y═OCCl₃)or carbonyl-diimidazole (Y=imidazole) or the like in a solvent such asdichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, orthe like and a base such as triethylamine, diisopropylethylamine,N-methylmorpholine, or the like. Alternatively, aminoalcohol 4-2 can beconverted to an appropriate carbamate by treatment with reagents such asdibenzyl dicarbonate or benzyl chloroformate in the presence of basessuch as triethylamine, diisopropylethylamine or the like in solventssuch as dichloromethane, dichloroethane, tetrahydrofuran,dimethoxyethane or the like. The carbamates can then be converted intooxazolidinones 4-3 by treating with bases like lithium-, sodium- orpotassium hexamethyldisilazide in solvents like tetrahydrofuran,dimethoxyethane or the like. Enantiopure products may be obtained viachiral chromatography.

Compounds of the present invention 5-5 wherein R, R^(a), p, A², A³ and nare as defined in the claims can be prepared as shown in Scheme 5.Appropriately substituted aminoalcohol 5-1 can be prepared as shown inScheme 4 and preferentially protected as a carbamate such as t-butylcarbamate (BOC) or benzyl carbamate (Cbz). Other carbamate andalternative protecting groups for nitrogen can be found in “ProtectiveGroups in Organic Synthesis”, 3^(rd) Ed. John Wiley and Sons, New York,pp 494. Protection of the nitrogen with a BOC or Cbz group can becarried out by reaction of 5-1 with di-t-butyldicarbonate ordibenzyldicarbonate in an appropriate solvent such as dichloromethane,dichloroethane, tetrahydrofuran, dimethoxyethane, or the like. Alcohol5-2 can be converted to azide 5-3 by reaction with methanesulfonylchloride in dichloromethane, dichloroethane, tetrahydrofuran,dimethoxyethane, or the like in the presence of an appropriate base suchas triethylamine, diisopropylethylamine, N-methylmorpholine, or thelike. Alternatively, the alcohol may be converted to an alternativeleaving group, such as tosylate, iodide, bromide, or the like. Themesylate is then displaced by an azide source, such as NaN₃, LiN₃,Bu₄NN₃ or the like in an appropriate solvent, such as DMF, DMPU, or thelike. Azide 5-3 can also be prepared by treatment of alcohol 5-2 withdiphenylphosphoryl azide, diethylazodicarboxylate and triphenylphosphinein THF. Azide 5-3 can be reduced by hydrogenation over a metal catalystsuch as PtO₂ or Pd/C or the like in an appropriate solvent, such asEtOAc, THF, EtOH, or the like. Following reduction and removal of theprotecting group diamine 5-4 is obtained. For the BOC protecting group,TFA/CH₂Cl₂ is the preferred method of removal; for the CBZ protectinggroup, hydrogenation over a metal catalyst, such as PtO₂ or Pd/C or thelike in an appropriate solvent, such as EtOAc, THF, EtOH, or the like isthe preferred method of removal. Diamines 5-4 are cyclized toimidazolidinones 5-5 using phosgene (Y═Cl) or a phosgene equivalent suchas triphosgene (Y═OCCl₃) or carbonyldiimidazole (Y=imidazole) or thelike in a solvent such as dichloromethane, dichloroethane,tetrahydrofuran, dimethoxyethane, or the like and a base such astriethylamine, diisopropylethylamine, N-methylmorpholine, or the like.Enantiopure products may be obtained via chiral chromatography.

Compounds of the present invention 6-4 wherein R, R^(a), p, A², A³ and nare as defined in the claims can be prepared as shown in Scheme 6.Treatment of 6-1 with an appropriately substituted protectedaminoaldehyde which can be purchased or prepared by known methods in thepresence of a reducing agent such as sodium borohydride, sodiumcyanoborohydride, sodium triacetoxyborohydride or the like in methanol,ethanol, dichloroethane, tetrahydrofuran or the like or according tomethods described in Smith, M. B. and March, J. “March's AdvancedOrganic Chemistry”, 5^(th) Ed., John Wiley and Sons, New York, pp.1187-1189 (2001) and references cited therein affords 6-2. Preferredconditions for this transformation are sodium cyanoborohydride inmethanol with catalytic acetic acid. Deprotection of 6-2 affords 6-3.For the BOC protecting group, TFA/CH₂Cl₂ is the preferred method ofdeprotection. Diamines 6-3 are then cyclized to imidazolidinones 6-4using phosgene (Y═Cl) or a phosgene equivalent such as triphosgene(Y═OCCl₃) or carbonyl-diimidazole (Y=imidazole) or the like in a solventsuch as dichloromethane, dichloroethane, tetrahydrofuran,dimethoxyethane, or the like and a base such as triethylamine,diisopropylethylamine, N-methylmorpholine, or the like. Enantiopureproducts may be obtained using chiral chromatography.

Compounds of the present invention 7-5 wherein R, R^(a), p, A², A³ and nare as defined in the claims can be prepared as shown in Scheme 7.Treatment of amine 7-1, prepared as described in Scheme 4 with anappropriate dicarbonate or chloroformate affords 7-2. 7-2 can beconverted to azide 7-3 by reaction with methanesulfonyl chloride indichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, orthe like in the presence of an appropriate base such as triethylamine,diisopropylethylamine, N-methylmorpholine, or the like. Alternatively,the alcohol may be converted to an alternative leaving group, such astosylate, iodide, bromide, or the like. The mesylate is then displacedby an azide source, such as NaN₃, LiN₃, Bu₄NN₃ or the like in anappropriate solvent, such as DMF, DMPU, or the like. Azide 7-3 can alsobe prepared by treatment of alcohol 5-2 with diphenylphosphoryl azide,diethylazodicarboxylate and triphenylphosphine in THF. Azide 7-3 can bereduced to amine 7-4 with H2 over PtO₂ with THF as a solvent when R₄ isbenzyl. Cyclization of 7-4 to imidazolidinones 7-5 is accomplishedthrough the use of an appropriate base, such as lithium diisopropylamideor lithium-, sodium-, or potassium bis(trimethylsilyl)amide or the likein an appropriate solvent, such as THF, dimethoxyethane, DMF, DMA, orthe like. Enantiopure products may be obtained via chiralchromatography.

Compound 8-1 (prepared as described in Schemes 5, 6, and 7) wherein R,R^(a), A², A³, p, and n are as defined in the claims can be converted to8-2 by treatment with an appropriate alkylating agent such as an alkylhalide, alkyl tosylate, alkyl mesylate, or the like (for example methyliodide) in an appropriate solvent such as THF, dimethoxyethane, DMF,DMA, or the like, in the presence of an appropriate base, such aslithium diisopropylamide or lithium-, sodium-, or potassiumbis(trimethylsilyl)amide or the like.

Intermediates 9-3 and 9-4 wherein R^(a), p, and A³ are as defined in theclaims utilized in the present invention can be prepared as shown inScheme 9. An appropriately substituted benzyl nitrile 9-1 prepared asshown in Scheme 2 can be heated with a base such as sodium hydroxide orpotassium hydroxide or the like in an appropriate aqueous alcohol suchas ethanol, propanol or the like to afford the appropriately substitutedbenzoic acid 9-2 (See: Smith, M. B. and March, J. “March's AdvancedOrganic Chemistry”, 5^(th) Ed., John Wiley and Sons, New York, pp.1179-1180 (2001) and references therein). Benzoic acids 9-2 can bereduced to benzyl alcohols 9-3 with reducing agents such as borane insolvents such as tetrahydrofuran or the like (See: Smith, M. B. andMarch, J. “March's Advanced Organic Chemistry”, 5^(th) Ed., John Wileyand Sons, New York, pp. 1549 (2001) and references therein).Alternatively, 9-2 can be esterified by known methods includingtreatment with trimethylsilyldiazomethane and the resulting esterreduced to alcohol 9-3 with LiAlH₄ or the like. Intermediates 9-3 can betransformed into benzyl bromides 9-4 using reagents such astriphenylphosphine and carbon tetrabromide in solvents such asdichloromethane, dichloroethane or the like (See: Smith, M. B. andMarch, J. “March's Advanced Organic Chemistry”, 5^(th) Ed., John Wileyand Sons, New York, pp. 518-519 (2001) and references therein).

Intermediates 10-4 of the present invention wherein R, R¹, A², p, and nare as defined in the claims can be prepared as shown in Scheme 10 froman appropriately substituted benzaldehyde 10-1 by condensation with anitroalkane to afford the substituted nitroalcohol 10-2. This reactionmay be catalyzed by aqueous bases such as sodium hydroxide or the likein solvents such as ethanol, methanol or the like. Nitroalcohols 10-2can be reduced to aminoalcohols 10-3 with reductants such as Raneynickel, palladium on activated carbon or platinum oxide in the presenceof hydrogen gas and aqueous acid in alcoholic solvents such as methanol,ethanol or the like (See: Langer, O., et al., Bioorg. Med. Chem., 2001,9, 677-694). Aminoalcohols 10-3 can be cyclised to oxazolidinones 10-4using reagents such as phosgene (Y═Cl), triphosgene (Y═OCCl₃) orcarbonyl diimidazole (Y=imidazole) with bases such as triethylamine,diisopropylethylamine or the like in solvents like dichloromethane,dichloroethane, tetrahydrofuran, dimethoxyethane or the like.

Intermediates 11-4 of the present invention wherein R, R¹, A², p and nare as defined in the claims can be prepared as shown in scheme 11.Treatment of an N-carbamoyl-(N-methoxy-N-methyl)amide of an amino acid11-1 which can be purchased or prepared by known methods with a Grignardor other organometallic reagent such as an organolithium affords thecorresponding ketone 11-2. Reduction of the ketone with sodiumborohydride or zinc borohydride in alcoholic solvents or THF or the likeor with other reducing agents such as phenyldimethyl silane in THFaffords alcohol 11-3 which can be cyclized to oxazolidinone 11-4 upontreatment with base such as KOH in solvents such as MeOH, EtOH or thelike and THF, dioxane, dimethoxyethane or the like.

Compounds of the present invention 12-3 wherein R, R¹, R^(a), A², A³, pand n are as defined in the claims can be prepared as shown in Scheme12. Oxazolidinones 12-2, prepared as shown in Schemes 10 and 11 can bealkylated with benzyl bromides 12-1 which is prepared as shown in Scheme9 using bases such as sodium hexamethyldisilazide or sodium hydride insolvents like tetrahydrofuran, dimethoxyethane, diethyl ether,dimethylformamide, dimethylacetamide, or the like to afford products12-3.

Compounds of the present invention 13-4 wherein R, R¹, R^(a), A², A³, pand n are as defined in the claims can be prepared as shown in Scheme13. Oxazolidinones 13-2, prepared as shown in Schemes 10 and 11 can bealkylated with benzyl bromides 13-1 which can be prepared as shown inScheme 1 using bases such as sodium hexamethyldisilazide or sodiumhydride in solvents like tetrahydrofuran, dimethoxyethane, diethyl etheror the like to afford products 13-3. Compounds 13-4 are then preparedvia a Suzuki or Stille reaction or variation thereof employing palladiumcatalyzed cross coupling of iodide 13-3 with an appropriatelysubstituted aryl- or heteroaryl-boronic acid, -boronate ester or-trialkyl tin as described in Miyaua et al., Chem. Rev. 95, 2457 (1995)and references cited within and as described in Smith, M. B. and March,J. “March's Advanced Organic Chemistry”, 5^(th) Ed., John Wiley andSons, New York, pp. 868-869 (2001) and references cited therein.

Compounds 14-5 of the present invention wherein R, R^(a), A², A³, p andn are as defined in the claims can be prepared as shown in Scheme 14.Benzyl alcohols 14-1 can be purchased or prepared according to theprocedure outline in Scheme 9. Reaction of 14-1 with the Dess-Martinperiodinane affords the corresponding benzylaldehydes 14-2. Othermethods for oxidizing a primary hydroxyl group to an aldehyde can alsobe used, for example, Swern oxidation conditions, tetrapropylammoniumperruthenate, pyridinium chlorochromate, sulfur trioxide-pyridine, orthe like. 2-Amino-1-phenylethanols 14-3 can be prepared from 14-2 viathe corresponding silylated cyanohydrin by treatment with trimethylsilylcyanide and catalytic zinc iodide followed by reduction with lithiumaluminum hydride or the like reducing agent. Alternatively,2-amino-1-phenylethanols 14-3 can be prepared from 14-2 via thecorresponding cyanohydrin by treatment with potassium cyanide followedby reduction. 2-Amino-1-phenylethanols 14-3 can be cyclized tooxazolidinones 14-4 using reagents such as phosgene (Y═Cl), triphosgene(Y═OCCl₃) or carbonyl diimidazole (Y=imidazole) with bases such astriethylamine, diisopropylethylamine or the like in solvents likedichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane or thelike. Oxazolidinones 14-4 can be alkylated with alkyl, heteroalkyl,aryl, or heteroaryl bromides using bases such as sodiumhexamethyldisilazide or sodium hydride in solvents like tetrahydrofuran,dimethoxyethane, diethyl ether or the like to afford products 14-5.Enantiopure products may be obtained via chiral chromatography.

Compounds 15-6 of the present invention wherein R, R¹ R^(a), A², A³, pand n are as defined in the claims can be prepared as shown in Scheme15. Aldehydes 15-1 can be purchased or prepared according to theprocedure outline in Scheme 1. Condensation of 15-1 with a nitroalkaneaffords the substituted nitroalcohols 15-2. This reaction may becatalyzed by aqueous bases such as sodium hydroxide or the like insolvents such as ethanol, methanol, or the like. Nitroalcohols 15-2 canbe reduced to aminoalcohols 15-3 with reductants such as Raney nickel,palladium on activated carbon, or platinum oxide in the presence ofhydrogen gas and aqueous acid in alcoholic solvents such as methanol,ethanol or the like (See: Langer, O., et al., Bioorg. Med. Chem., 2001,9, 677-694). Aminoalcohols 15-3 can be cyclized to oxazolidinones 15-4using reagents such as phosgene (Y═Cl), triphosgene (Y═OCCl₃) orcarbonyl diimidazole (Y=imidazole) with bases such as triethylamine,diisopropylethylamine or the like in solvents like dichloromethane,dichloroethane, tetrahydrofuran, dimethoxyethane or the like.Oxazolidinones 15-5 are prepared via a Suzuki or Stille reaction orvariation thereof employing palladium catalyzed cross coupling ofiodides 15-4 with appropriately substituted aryl- or heteroaryl-boronicacids, -boronate esters or -trialkyl tin compounds, as described inMiyaura et al., Chem. Rev. 95, 2457 (1995) and references cited within,and as described in Smith, M. B. and March, J. “March's Advanced OrganicChemistry”, 5^(th) Ed., John Wiley and Sons, New York, pp. 868-869(2001) and references cited therein. Oxazolidinones 15-5 can bealkylated with alkyl, heteroalkyl, aryl, or heteroaryl bromides usingbases such as sodium hexamethyldisilazide or sodium hydride in solventslike tetrahydrofuran, dimethoxyethane, diethyl ether or the like toafford products 15-6. Enantiopure products may be obtained via chiralchromatography.

Compounds 16-5 of the present invention wherein R, R¹ R^(a), A², A³, pand n are as defined in the claims can be prepared as shown in Scheme16. Aldehydes 16-1 can be purchased or prepared according to theprocedure outline in Scheme 1. Condensation of 16-1 with chiralN-acyloxazolidinones affords the aldol adducts 16-2, as described inEvans, D. A. et al., J. Am. Chem. Soc., 2002, 124, 392-3. The chiralN-acyloxazolidinones can be purchased or prepared as described in Ager,D. J.; Allen, D. A.; Schaad, D. R. Synthesis 1996, 1283-5. Compounds16-2 can be hydrolyzed to the corresponding acids and then treated withdiphenylphosphorazidate and a trialkylamine base to effect a Curtiusrearrangement, affording chiral oxazolidinones 16-3. Oxazolidinones 16-4are prepared via a Suzuki or Stille reaction or variation thereofemploying palladium catalyzed cross coupling of iodides 16-3 withappropriately substituted aryl- or heteroaryl-boronic acids, -boronateesters or -trialkyl tin compounds, as described in Miyaura et al., Chem.Rev. 95, 2457 (1995) and references cited within, and as described inSmith, M. B. and March, J. “March's Advanced Organic Chemistry”, 5^(th)Ed., John Wiley and Sons, New York, pp. 868-869 (2001) and referencescited therein. Oxazolidinones 16-4 can be alkylated with alkyl,heteroalkyl, aryl, or heteroaryl bromides using bases such as sodiumhexamethyldisilazide or sodium hydride in solvents like tetrahydrofuran,dimethoxyethane, diethyl ether or the like to afford products 16-5.Alternatively, oxazolidinones 16-3 are alkylated with the appropriatebromides to afford compounds 16-6, which are subjected to a Suzuki orStille reaction or variation thereof with appropriately substitutedaryl- or heteroaryl-boronic acids, -boronate esters or -trialkyl tincompounds to afford products 16-5.

Example 1

2-Amino-5-(trifluoromethyl)benzonitrile

A 2-liter flask was charged with 100 g (0.348 mol) of4-amino-3-iodobenzotrifluoride, 40 g of CuCN and 750 mL of DMF. Themixture was heated to and then maintained at reflux for 1 hour. Thereaction was cooled and poured into 3 L of water containing 300 mL ofconcentrated ammonium hydroxide. To the mixture was added 1 L CH₂Cl₂.The mixture was then filtered through celite. The layers were separatedand the aqueous layer was back extracted with CH₂Cl₂. The organicextracts were combined and the solvent removed under reduced pressure.The residue was dissolved in 1.5 L of ether and the resulting solutionwas washed with 1N ammonium hydroxide, aqueous sodium bisulfate, 1Naqueous HCl and brine. The solution was dried over anhydrous MgSO₄ andfiltered through a silica gel plug containing a layer of MgSO₄ on top.The plug was washed with 0.5 L ether. The ether solutions were combinedand concentrated to 750 mL and let stand at room temperature. After 2days the resulting solids were collected, washed with hexanes and driedunder reduced pressure to afford 2-amino-5-(trifluoromethyl)benzonitrile¹H NMR (CDCl₃, 500 MHz) δ 7.68 (s, 1H), 7.58 (d, J=8.5 Hz, 1H), 6.81 (d,J=8.5 Hz, 1H), 4.80 (br s, 2H).

Example 2

2-Iodo-5-(trifluoromethyl)benzonitrile

To a solution of 2-amino-5-(trifluoromethyl)benzonitrile (15.1 g) anddiiodomethane (24 mL) in acetonitrile (150 mL) at 35° C. was addedt-butyl nitrite (21 mL) dropwise. The reaction was maintained at 30-35°C. during the addition. The reaction was aged for 30 min and then washeated to 60° C. for 30 minutes. The reaction mixture was cooled,diluted with ether and washed 2× with water, 2× with aqueous sodiumbisulfite, water and then brine. The solution was dried over anhydrousMgSO₄, filtered through a silica gel plug and then concentrated giving100 g of a red oil. The product was purified by silica gelchromatography eluting sequentially with hexanes, 3:1 hexanes/CH₂Cl₂ and1:1 hexanes/CH₂Cl₂ to afford 2-iodo-5-(trifluoromethyl)benzonitrile. ¹HNMR (CDCl₃, 500 MHz) δ 8.10 (d, J=8.5 Hz, 1H), 7.85 (d, J=1.8 Hz, 1H),7.52 (dd, J=8.5, 1.8 Hz, 1H).

Example 3

5′-Isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile

To a solution of 2-iodo-5-(trifluoromethyl)benzonitrile (2.0 g, 6.7mmol) and (5-isopropyl-2-methoxyphenyl)boronic acid (1.6 g, 8.4 mmol) indimethyl ethylene glycol (30.4 mL) was added 2M Na₂CO₃ (6.8 mL), ethanol(9.6 mL), and water (10 mL). The solution was degassed with nitrogen for2 minutes. Pd(PPh₃)₄ (774 mg, 0.67 mmol) was added and the solution wasdegassed with nitrogen again for 2 minutes. The solution was dividedequally into two 40 mL microwave tubes. Each tube was degassed withnitrogen for 1 minute, sealed, and placed in a microwave reactor. Thewattage was set for 200 W until the temperature reached 150° C. and thenthe temperature was held at 150° C. for ten minutes. The tubes were thencooled to room temperature, combined, poured into H₂O (50 mL), andextracted with EtOAc (100 mL). The organic layer was washed with brine(50 mL), dried over Na₂SO₄, filtered, and concentrated. Purification byflash chromatography with 15% CH₂Cl₂/hexanes afforded5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile as alight yellow oil. R_(f)=0.65 (25% EtOAc/hexanes). ¹H NMR (CDCl₃, 500MHz) δ 7.97 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H),7.31 (dd, J=8.5, 2.0 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 6.97 (d, J=8.5 Hz,1H), 3.82 (s, 3H), 2.93 (m, 1H), 1.27 (d, J=7.0 Hz, 6H).

Example 4

1-[5′-Isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanamine

5′-Isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile(996.2 mg, 3.12 mmol) was dissolved in Et₂O (33 mL) and cooled to 0° C.LAH (12.49 mL of a 1 M solution in Et₂O, 12.49 mmol) was added dropwiseby syringe. After stirring at 0° C. for 10 minutes, the reaction waswarmed to room temperature and stirred at room temperature for 6 hours.The reaction was then quenched by slow dropwise addition of 1.5 mL ofH₂O (vigorous evolution of gas), followed by 1.5 mL of 30% NaOH,followed by 3.0 mL of H₂O. The resulting gelatinous precipitate waswashed with 5×20 mL of CH₂Cl₂; the organic washes were dried overNa₂SO₄, filtered and concentrated. Purification of the residue by flashchromatography with 2% MeOH/CH₂Cl₂ containing 0.1% Et₃N afforded1-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanamine.R_(f)=0.30 (10% MeOH/CH₂Cl₂). LCMS=324.3 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz)δ 7.77 (s, 1H), 7.55 (d, J=6.8 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.25(dd, J=8.3, 2.1 Hz, 1H), 7.00 (d, J=2.1 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H),3.66-3.74 (m, 5H), 2.91 (m, 1H), 1.26 (d, J=6.9 Hz, 6H).

Example 5

4-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-oneStep A: methyl [3,5-bis(trifluoromethyl)phenyl](hydroxy)acetate

To solution of [3,5-bis(trifluoromethyl)phenyl](hydroxy)acetic acid (510mg, 1.77 mmol) in benzene (10 mL) was added MeOH (1.5 mL) followed by(trimethylsilyl)diazomethane (1.06 mL of a 2M solution in hexanes, 2.12mmol). After 10 minutes, the reaction was quenched with several drops ofHOAc (add until yellow color disappears). The reaction was concentratedand purified by flash chromatography with 10 to 80% EtOAc/hexanes toafford methyl [3,5-bis(trifluoromethyl)phenyl](hydroxy)acetate. ¹H NMR(CDCl₃, 500 MHz) δ 7.94 (s, 2H), 7.85 (s, 1H), 5.32 (s, 1H), 3.83 (s,3H), 3.68 (bs, 1H).

Step B: methyl [3,5-bis(trifluoromethyl)phenyl](bromo)acetate

Methyl [3,5-bis(trifluoromethyl)phenyl](hydroxy)acetate (300 mg, 0.993mmol) was dissolved in CH₂Cl₂ (10 mL). The solution was cooled to 0° C.and CBr₄ (659 mg, 1.986 mmol) was added followed by PPh₃ (521 mg, 1.986mmol). After 1 hour, the reaction was warmed to room temperature andstirred at room temperature for 1 hour. The reaction was filteredthrough a short plug of silica gel with CH₂Cl₂. The filtrate wasconcentrated and the residue was purified by flash chromatography with5% EtOAc/hexanes to afford methyl[3,5-bis(trifluoromethyl)phenyl](bromo)acetate. R_(f)=0.24 (5%EtOAc/hexanes). ¹H NMR (CDCl₃, 500 MHz) δ 8.02 (s, 2H), 7.87 (s, 1H),5.41 (s, 1H), 3.83 (s, 3H).

Step C: methyl[3,5-bis(trifluoromethyl)phenyl]({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)acetate

To a flask containing methyl[3,5-bis(trifluoromethyl)phenyl](bromo)acetate (237.7 mg, 0.651 mmol)was added1-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methenamine(102.1 mg, 0.316 mmol) in CH₂Cl₂ (4 mL). The reaction was stirred atroom temperature for 5 hours and then diluted with EtOAc (50 ml). Theorganic solution was washed with water and brine (15 mL each). Theorganic extract was dried over Na₂SO₄, filtered, and concentrated.Purification of the residue by flash chromatography (5 to 15%EtOAc/hexanes) affordedmethyl[3,5-bis(trifluoromethyl)phenyl]({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)acetate.R_(f)=0.33 (15% EtOAc/hexanes). LCMS=608.4 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.76-7.79 (m, 3H), 7.62 (s, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.31 (d,J=7.8 Hz, 1H), 7.23 (dd, J=8.2, 1.9 Hz, 1H), 6.96 (m, 1H), 6.89 (d,J=8.5 Hz, 1H), 4.30 (m, 1H), 3.54-3.70 (m, 8H), 2.87 (m, 1H), 1.21-1.23(m, 6H).

Step D:2-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-methyl}amino)ethanol

A solution ofmethyl[3,5-bis(trifluoromethyl)phenyl]({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)acetate(13.2 mg, 0.0217 mmol) was dissolved in Et₂O (1.5 mL) and cooled to 0°C. LAH (108.5 μL of a 1 M solution in LAH, 0.1085 mmol) was addeddropwise by syringe. The reaction was warmed to room temperature andstirred at room temperature for 1 hour. The reaction was then quenchedby addition of H₂O (100 μL) followed by 1 N NaOH (100 μL), followed byH₂O (300 μL). The gelatinous precipitate was washed several times withCH₂Cl₂. The organic washes were filtered through a plug of silica gelwith 2% MeOH/CH₂Cl₂ and the filtrate was concentrated. Purification ofthe residue by PTLC with 25% EtOAc/hexanes afforded2-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol.R_(f)=0.27 (25% EtOAc/hexanes). LCMS=580.4 (M+1)⁺. ¹H NMR (CD₂Cl₂, 500MHz) δ 7.79 (s, 1H), 7.75 (s, 2H), 7.63-7.68 (m, 1H), 7.55 (d, J=7.8 Hz,1H), 7.31 (d, J=7.8 Hz, 1H), 7.23 (m, 1H), 6.94 (m, 1H), 6.89 (m, 1H),3.43-3.76 (m, 9H), 2.86 (m, 1H), 1.90 (bs, 1H), 1.20 (d, J=6.8 Hz, 6H).

Step E:4-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one

To a solution of phosgene (21 μL of a 20% solution in toluene, ˜0.0535mmol) in CH₂Cl₂ (0.5 mL) was added2-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol(3.1 mg, 0.00535 mmol) in CH₂Cl₂ (0.5 mL), followed by DIPEA (19 μL,0.107 mmol). After stirring for 5 minutes, the reaction was poured intowater (1 mL) and the mixture was extracted with EtOAc (20 mL). Theorganic extract was washed with H₂O, saturated NaHCO₃, and brine (5 mLeach). The organic layer was then dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by PTLC to afford4-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one.R_(f)=0.27 (25% EtOAc/hexanes). LCMS=606.3 (M+1)⁺. ¹H NMR (CD₂Cl₂, 500MHz) (Doubling of some peaks observed; atropisomers present in 1:1ratio) δ 7.84 (s, 1H), 7.19-7.60 (m, 6H), 6.80-6.87 (m, 2H), 3.84-4.68(m, 5H), 3.68 & 3.64 (2 singlets, 3H), 2.82 (m, 1H), 1.17-1.21 (m, 6H).

Example 6

5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-oneStep A: 2-[3,5-bis(trifluoromethyl)phenyl]oxirane

In a dry flask was placed NaH (1.09 g of 60% NaH, 27.27 mmol). DMSO (90mL) was added followed by trimethylsulfoxonium iodide (7.0 g, 31.82mmol). The reaction was stirred for 5 minutes and then3,5-bis(trifluoromethyl)benzaldehyde (1.5 mL, 9.09 mmol) was added as asolution in DMSO (15 mL). The reaction was stirred at room temperaturefor 1 hour and then poured into ice/water (300 mL). The mixture wasextracted with pentanes (3×150 mL). The pentane extracts were combinedand filtered through a short plug of silica gel with 10% Et₂O/pentanes.The filtrate was concentrated and the residue was purified by flashchromatography with 10% Et₂O/pentanes to give2-[3,5-bis(trifluoromethyl)phenyl]oxirane. R_(f)=0.42 (10%Et₂O/pentanes). ¹H NMR (CDCl₃, 500 MHz) 7.82 (s, 1H), 7.74 (s, 2H), 3.99(dd, J=3.9, 2.5 Hz, 1H), 3.23 (dd, J=5.2, 4.1 Hz, 1H), 2.79 (dd, J=5.5,2.5 Hz, 1H).

Step B:1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol

A solution of1-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methenamine(300 mg, 0.929 mmol) and 2-[3,5-bis(trifluoromethyl)phenyl]oxirane (297mg, 1.161 mmol) in 2-propanol (9 mL) was heated at reflux for 15 hoursand then cooled to room temperature. The solution was concentrated, andpurification of the residue by flash chromatography with 10 to 80%EtOAc/hexanes afforded1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol.R_(f)=0.24 (25% EtOAc/hexanes). LCMS=580.3 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.75-7.76 (m, 3H), 7.69 (s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.34 (d,J=7.7 Hz, 1H), 7.25 (m, 1H), 6.98 (bs, 1H), 6.92 (d, J=8.5 Hz, 1H), 4.62(m, 1H), 3.65-3.82 (m, 5H), 2.89 (m, 1H), 2.79 (dd, J=12.4, 3.0 Hz, 1H),2.48 (m, 1H), 1.23 (d, J=6.8 Hz, 6H).

Step C:5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one

To a solution of1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol(31.9 mg, 0.0551 mmol) in CH₂Cl₂ (5 mL) at 0° C. was added DIPEA (67 μL,0.386 mmol), followed by triphosgene (8.2 mg, 0.0276 mmol). The reactionwas stirred at 0° C. for 30 minutes. The reaction was then poured intosaturated NaHCO₃ (15 mL) and the mixture was extracted with EtOAc (50mL). The organic layer was washed with brine (15 mL), dried over Na₂SO₄,filtered, and concentrated. Purification of the residue by flashchromatography (20% EtOAc/hexanes) afforded5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one.R_(f)=0.32 (25% EtOAc/hexanes). LCMS=606.3 (M+1)⁺. ¹H NMR (CD₂Cl₂, 500MHz) (atropisomers present in 1:1 ratio, doubling of some peaks) δ 7.90(s, 1H), 7.77 (s, 2H), 7.57-7.62 (m, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.27(m, 1H), 6.98 (s, 1H), 6.93 (dd, J=8.4, 3.2 Hz, 1H), 5.42-5.53 (m, 1H),4.15-4.59 (m, 2H), 3.72 & 3.73 (2 singlets, 3H), 3.05-3.65 (m, 2H), 2.88(m, 1H), 1.19-1.23 (m, 6H).

The 2 enantiomers could be separated by chiral HPLC using 15%IPA/heptanes and an AD chiral column.

Example 7

3-{[5′-Isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-pyridin-2-yl-1,3-oxazolidin-2-oneStep A:2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)-1-pyridin-2-ylethanol

A solution of1-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methenamine(300 mg, 0.929 mmol) and 2-oxiran-2-ylpyridine (640 mg) [prepared byreaction of 2-pyridine carboxaldehyde with NaH and trimethylsulfoxoniumiodide in DMSO] in 2-propanol (9 mL) was heated at reflux for 5 hoursand then cooled to room temperature. The solution was concentrated, andthe residue was purified by flash chromatography with 50 to 100%EtOAc/hexanes containing 0.5% Et₃N to afford2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)-1-pyridin-2-ylethanol.Analysis by LCMS showed the desired product contaminated with severalminor impurities. This material was used in the next reaction withoutfurther purification or analysis.

Step B: Benzyl(2-hydroxy-2-pyridin-2-ylethyl){[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate

A solution of (PhCH₂OCO)₂O (103 mg, 0.360 mmol) in dry CH₂Cl₂ (2 mL) wasadded by cannula to a stirred solution of2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)-1-pyridin-2-ylethanol(160 mg, 0.360 mmol) in dry CH₂Cl₂ (10 mL) at room temperature under N₂.The reaction was stirred for 2 h at room temperature and concentrated invacuo to give the crude product. This was purified by flashchromatography (Si, 25×160 mm, 0-50% EtOAc in hexanes gradient) toafford benzyl (2-hydroxy-2-pyridin-2-ylethyl){[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate.R_(f)=0.63 (50% EtOAc/hexanes). LCMS calc.=579.25; found=579.2 (M+1)⁺.

Step C:3-{[5′-Isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-pyridin-2-yl-1,3-oxazolidin-2-one

A solution of potassium bis(trimethylsilyl)amide (464 μL of a 0.5Msolution in toluene, 0.232 mmol) was added dropwise to a stirredsolution of benzyl(2-hydroxy-2-pyridin-2-ylethyl){[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate(134.3 mg, 0.232 mmol) in dry THF (10 mL) at room temperature under N₂.After stirring at room temperature for 1 h, the reaction was quenchedwith saturated NH₄Cl (10 mL) and extracted with EtOAc (3×20 mL). Thecombined extracts were dried (Na₂SO₄) and concentrated in vacuo to givethe crude product. This was purified by flash chromatography (Si, 25×160mm, 0-70% EtOAc in hexanes gradient) to afford3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-pyridin-2-yl-1,3-oxazolidin-2-one.R_(f)=0.58 (50% EtOAc/hexanes). LCMS calc.=471.19; found=471.2 (M+1)⁺.

Example 8

5′-Isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carboxylic acid

A solution of5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (727mg, 2.28 mmol) and KOH (767 mg, 13.7 mmol) in H₂O (7.70 mL) and i-PrOH(11.55 mL) was subjected to microwave irradiation (300 W 130° C., 4 h)in a sealed tube. The reaction mixture was concentrated in vacuo toremove the i-PrOH. The aqueous slurry obtained was diluted with water(50 mL) and extracted with EtOAc (50 mL). The organic extract was dried(Na₂SO₄) and concentrated in vacuo to afford5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carboxamide. Theaqueous layer was acidified with concentrated HCl and extracted withEtOAc (3×50 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo to give5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carboxylic acid asa colorless solid. ¹H NMR (CDCl₃, 500 MHz) δ 8.01 (s, 1H), 7.71 (d,J=7.8 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.14 (d, J=8.1 Hz, 1H), 7.04 (s,1H), 6.77 (d, J=8.1, 1H), 3.68 (s, 3H), 2.84 (septet, J=6.7 Hz, 1H),1.19 (d, J=6.7 Hz, 6H).

Example 9

[5′-Isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol

A solution of borane in THF (1 M, 859 μL, 0.859 mmol) was added dropwiseto a stirred solution of5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carboxylic acidand 5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carboxamide(3:1, 96.8 mg, 0.286 mmol) in dry THF at room temperature under N₂. Thereaction was stirred at room temperature for 3 h and carefully quenchedwith water (10 mL). The mixture was extracted with EtOAc (3×20 mL) andthe combined extracts were washed with brine, dried (Na₂SO₄) andconcentrated in vacuo to give the crude product. This was purified byflash chromatography (Si, 125×160 mm, 0-30% EtOAc in hexanes gradient)to afford[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol as acolorless oil. R_(f)=0.27 (10% EtOAc/hexanes). ¹H NMR (CDCl₃, 500 MHz) δ7.89 (br s, 1H), 7.62 (dd, J=8.0, 1.3 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H),7.29 (dd, J=8.5, 2.3 Hz, 1H), 7.03 (d, J=2.3 Hz, 1H), 6.96 (d, J=8.5,1H), 4.51 (m, 2H), 3.74 (s, 3H), 2.93 (septet, J=7.0 Hz, 1H), 2.51 (s,1H), 1.29 (d, J=7.0 Hz, 6H).

Example 10

2-(Bromomethyl)-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl

CBr₄ (112 mg, 0.211 mmol) and Ph₃P (55 mg, 0.211 mmol) were addedsuccessively to a stirred solution of[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol (57.1mg, 0.176 mmol) in dry CH₂Cl₂ (1 mL) at 0° C. under N₂. The solution wasstirred at room temperature for 1 h and the reaction mixture wasconcentrated in vacuo to afford the crude product. This was purified byflash chromatography (Si, 12×160 mm, 0-20% EtOAc in hexanes gradient) togive 2-(bromomethyl)-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenylas a colorless oil. R_(f)=0.95 (20% EtOAc/hexanes). LCMS calc.=387.05;found=387.0 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.83 (br s, 1H), 7.60 (dd,J=8.0, 1.3 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.29 (dd, J=8.5, 2.3 Hz,1H), 7.14 (d, J=2.3 Hz, 1H), 6.95 (d, J=8.5, 1H), 4.45 (d, J=10.6 Hz,1H), 4.33 (d, J=10.6 Hz, 1H), 3.76 (s, 3H), 2.94 (septet, J=6.9 Hz, 1H),1.29 (d, J=6.9 Hz, 6H).

Example 11

1-(4-Methylphenyl)-2-nitroethanol

A stirred solution of 4-methylbenzaldehyde (325 mg, 319 μL, 2.71 mmol)and nitromethane (531 μL, 9.89 mmol) in absolute EtOH (20 mL) at 0° C.was treated with 10% aq. NaOH (m/v) (1.14 mL, 2.84 mmol), stirred for 1h and treated with 2% aq. acetic acid (m/v) (8.54 mL, 2.84 mmol). Thereaction was stirred for 1 h at room temperature then partitionedbetween water (50 mL) and EtOAc (50 mL). The aqueous layer was extractedwith EtOAc (2×50 mL) and the combined organic extracts were washed withsaturated NaHCO₃ (50 mL) and brine (50 mL), dried (Na₂SO₄) andconcentrated in vacuo to afford 1-(4-methylphenyl)-2-nitroethanol as acolorless oil. ¹H NMR (CDCl₃, 500 MHz) δ 7.28 (d, J=8.1 Hz, 2H), 7.21(d, J=8.1 Hz, 2H), 5.42 (dt, J=9.6, 3.3 Hz, 1H), 4.60 (dd, J=13.3, 9.7Hz, 1H), 4.49 (dd, J=13.3, 3.1 Hz, 1H), 2.79 (d, J=3.7, 1H), 2.36 (s,3H).

Example 12

2-Amino-1-(4-methylphenyl)ethanol

A suspension of 10% Pd/C (24 mg) in a solution of1-(4-methylphenyl)-2-nitroethanol (50 mg, 0.276 mmol) in absolute EtOH(1 mL) was stirred overnight at room temperature under 15 psi of H2. Thereaction mixture was filtered through a pad of Celite and the filtratewas concentrated in vacuo to afford 2-amino-1-(4-methylphenyl)ethanol asan oil. LCMS calc.=152.10; found=152 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ7.20 (d, J=8.0 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 4.57 (dd, J=7.9, 3.9 Hz,1H), 2.86 (dd, J=12.7, 3.9 Hz, 1H), 2.76 (dd, J=12.7, 7.9 Hz, 1H), 2.33(s, 3H).

Example 13

5-(4-Methylphenyl)-1,3-oxazolidin-2-one

Diisopropylethylamine (181 mg, 244 μL, 1.40 mmol) and triphosgene (138mg, 0.466 mmol) were added successively to a stirred solution of2-amino-1-(4-methylphenyl)ethanol (35.2 mg, 0.233 mmol) in dry CH₂Cl₂(22 mL) at 0° C. under N₂. The reaction was stirred at 0° C. for 1 hthen concentrated in vacuo to a volume of about 5 mL. The mixture wasdiluted with water (50 mL) and extracted with EtOAc (3×50 mL). Thecombined organic extracts were dried (Na₂SO₄) and concentrated in vacuoto give the crude product. This was purified by flash chromatography(Si, 12×160 mm, 0-80% EtOAc in hexanes gradient) to afford5-(4-methylphenyl)-1,3-oxazolidin-2-one. R_(f)=0.41 (50% EtOAc/hexanes).LCMS calc.=178.08; found=178.1 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.25(d, J=7.4 Hz, 2H), 7.19 (d, J=7.4 Hz, 2H), 6.69 (br s, 1H), 5.55 (t,J=7.8 Hz, 1H), 3.93 (t, J=8.6 Hz, 1H), 3.52 (t, J=8.1 Hz, 1H), 2.35 (s,3H).

Example 14

3-{[5′-Isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-(4-methylphenyl)-1,3-oxazolidin-2-one

Sodium hydride (6.4 mg of a 60% dispersion in mineral oil, 0.161 mmol)was added to a stirred solution of5-(4-methylphenyl)-1,3-oxazolidin-2-one (37.7 mg, 0.0973 mmol) in dryTHF (1 mL) at room temperature under N₂. The reaction was stirred for 30min and a solution of2-(bromomethyl)-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl(19.0 mg, 0.107 mmol) in dry THF (2 mL) was added by cannula. Thereaction was stirred at room temperature for 3 days. The reaction wasquenched with saturated NH₄Cl (10 mL) and extracted with EtOAc (3×20mL). The combined organic extracts were washed with brine (10 mL), dried(Na₂SO₄) and concentrated in vacuo to give the crude product. This waspurified by flash chromatography (Si, 12×160 mm, 0-80% EtOAc in hexanesgradient) to afford3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-(4-methylphenyl)-1,3-oxazolidin-2-oneas a colorless oil. R_(f)=0.37 (20% EtOAc/hexanes). LCMS calc.=484.21;found=484.2 (M+1)⁺. ¹H NMR (benzene-d₆, 500 MHz, 1:1 mixture ofatropisomers) δ 7.76 (s, 0.5H), 7.65 (s, 0.5H), 7.31 (d, J=7.7 Hz, 1H),7.08 (dd, J=8.4, 2.4 Hz, 1H), 7.05 (br d, J=7.8 Hz, 1H), 6.95-6.86 (m,5H), 6.58 (t, J=7.7 Hz, 1H), 4.74 (t, J=8.0 Hz, 0.5H), 4.70 (t, J=8.0Hz, 0.5H), 4.50 (d, J=15.7 Hz, 0.5H), 4.42 (d, J=15.7 Hz, 0.5H), 4.25(d, J=15.7 Hz, 0.5H), 4.11 (d, J=15.7 Hz, 0.5H), 3.26 (s, 1.5H), 3.21(s, 1.5H), 2.81 (t, J=8.6 Hz, 0.5H), 2.76 (septet, J=7.0 Hz, 1H), 2.68(t, J=8.6 Hz, 0.5H), 2.55 (t, J=8.6 Hz, 0.5H), 2.53 (t, J=8.6 Hz, 0.5H),2.04 (s, 3H), 1.20 (t, J=7.0 Hz, 3H), 1.19 (t, J=7.0 Hz, 3H).

Example 15

1-[3,5-Bis(trifluoromethyl)phenyl]-2-nitropropan-1-ol

A stirred solution of 3,5-bis(trifluoromethyl)benzaldehyde (1.00 g, 4.13mmol) and nitroethane (1.13 g, 1.08 mL, 15.1 mmol) in absolute EtOH (20mL) at 0° C. was treated with 10% aq. NaOH (m/v) (1.73 mL, 4.34 mmol),stirred for 1 h and treated with 2% aq. acetic acid (m/v) (13.0 mL, 4.32mmol). The reaction was stirred for 1 h at room temperature thenpartitioned between water (50 mL) and EtOAc (50 mL). The aqueous layerwas extracted with EtOAc (2×50 mL) and the combined organic extractswere washed with saturated NaHCO₃ (50 mL) and brine (50 mL), dried(Na₂SO₄) and concentrated in vacuo to afford a 1.5:1 mixture of threo-and erythro-1-[3,5-bis(trifluoromethyl)phenyl]-2-nitropropan-1-ol as acolorless oil. ¹H NMR (CDCl₃, 500 MHz) threo-diastereoisomer: δ 7.88 (brs, 1H), 7.86 (br s, 2H), 5.22 (d, J=8.4 Hz, 1H), 4.77 (dq, J=8.4, 6.9Hz, 1H), 3.03 (br s 1H), 1.42 (d, J=6.9 Hz, 3H),erythro-diastereoisomer: δ 7.90 (br s, 1H), 7.86 (br s, 2H), 5.59 (d,J=3.2 Hz, 1H), 4.72 (dq, J=3.2, 6.9 Hz, 1H), 3.03 (br s 1H), 1.50 (d,J=6.9 Hz, 3H).

Example 16

2-Amino-1-[3,5-bis(trifluoromethyl)phenyl]propan-1-ol

A suspension of Raney Nickel (50 mg) in a solution of a 1.5:1 mixture ofthreo- and erythro-1-[3,5-bis(trifluoromethyl)phenyl]-2-nitropropan-1-ol(50 mg, 0.158 mmol) in 30% (v/v) aqueous HCO₂H (0.75 mL) and MeOH (10mL) was stirred overnight at room temperature under 15 psi of H₂. Thereaction mixture was filtered through a pad of Celite and the filtratewas concentrated in vacuo to remove the MeOH. The aqueous slurry wasadjusted to pH 9-10 with 28% aq NH₄OH, diluted with water (20 mL) andextracted with EtOAc (3×20 mL). The combined extracts were washed withbrine (10 mL), dried (Na₂SO₄) and concentrated in vacuo to afford amixture of threo- anderythro-2-amino-[3,5-bis(trifluoromethyl)phenyl]propan-1-ol as colorlesssolid. LCMS calc.=288.08; found=288.1 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz)threo-diastereoisomer: δ 7.79 (br s, 3H), 4.35 (br s, 1H), 3.25 (br s,1H), 2.59 (br s, 3H), 0.86 (d, J=6.1 Hz, 3H), erythro-diastereoisomer: δ7.79 (br s, 3H), 4.71 (br s, 1H), 3.00 (br s, 1H), 2.59 (br s, 3H), 1.06(d, J=5.0 Hz, 3H).

Example 17

5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

Diisopropylethylamine (106 mg, 142 μL, 0.817 mmol) and triphosgene (20.2mg, 0.068 mmol) were added successively to a stirred solution of2-Amino-1-[3,5-bis(trifluoromethyl)phenyl]propan-1-ol (39.1 mg, 0.136mmol) in dry CH₂Cl₂ (10 mL) at 0° C. under N₂. The reaction was stirredat 0° C. for 1 h then concentrated in vacuo to a volume of about 5 mL.The mixture was diluted with water (50 mL) and extracted with EtOAc(3×50 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo to give the crude product. This was purified byflash chromatography (Si, 12×160 mm, 0-70% EtOAc in hexanes gradient) toaffordthreo-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(17.5 mg) anderythro-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(14.4 mg) as colorless solids. threo-diastereoisomer: R_(f)=0.63 (50%EtOAc/hexanes). LCMS calc.=314.06; found=314.1 (M+1)⁺. ¹H NMR (CDCl₃,600 MHz) δ 7.90 (br s, 1H), 7.83 (br s, 2H), 6.71 (br s, 1H), 5.17 (d,J=7.0 Hz, 1H), 3.86 (br pentet, J=6.2 Hz, 1H), 1.48 (d, J=6.2 Hz, 1H).This compound was separated into its enantiomers(4R,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-oneand(4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-oneusing chiral HPLC (AS column, 20×250 mm, 20% i-PrOH in heptane).erythro-diastereoisomer: R_(f)=0.38 (50% EtOAc/hexanes). LCMScalc.=314.06; found=314.1 (M+1)⁺. NMR (CDCl₃, 600 MHz) δ 7.90 (br s,1H), 7.79 (br s, 2H), 5.83 (d, J=8.0 Hz, 1H), 5.34 (br s, 1H), 4.31 (brpentet, J=7.0 Hz, 1H), 0.84 (d, J=6.6 Hz, 1H). This compound wasseparated into its two enantiomers(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-oneand(4R,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-oneusing chiral HPLC (AS column, 20×250 mm, 15% i-PrOH in heptane).

Chiral Synthesis of(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

This intermediate can be made directly from the chiral starting materialCBZ-L-alanine by the 3-step route shown below. The compound(4R,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-onecan be made by an analogous route starting from CBZ-D-alanine.

CBZ-L-Alanine (6.5 kg, 28.5 mol), HOBT-hydrate (4.8 kg, 34.8 mol),Weinreb amine-HCl salt (3.4 kg, 36.2 mol) and THF (32 L) are charged toa clean flask under nitrogen. The mixture is cooled to 0-10° C. and thenDIPEA (12.4 L) is slowly added at a temperature less than 25° C. EDC-HCl(7 Kg, 36.2 mol) is then added slowly with cooling at 15°-25° C. Theslurry is aged overnight at 20°-25° C. The mixture is then cooled to0°-10° C. and 3 N HCl (12 L) is added slowly. Then IPAC (32 L) is addedand the layers are separated. The organic layer is washed once with HCl(13 L) and twice with 8% NaHCO₃ (13 L) (CAUTION: FOAMING). The organiclayer is then concentrated under vacuum to about 15 L at 50° C. Theclear solution is cooled slowly to room temperature, allowing theproduct to crystallize. Heptane (˜70 L) is then added slowly. The slurryis filtered, washed with heptane (18 L), and dried at room temperatureon the filter pot. Product is obtained with >99.9% ee measured by chiralHPLC.

The Weinreb amide from Step 1 (6 kg, 22.5 mol) and3,5-bis(trifluoromethyl)bromobenzene (4.85 L, 28.1 mol) are dissolved inanhydrous THF (24 L). The solution is purged with nitrogen to removeoxygen. The water content should be <500 ppm at this point. Atmosphericdistillation can be carried out to azeotropically remove water ifnecessary. The solution is cooled to −10° C. and iso-PrMgCl in THF (56.4mol) is slowly added (2 hours) to the reaction via addition funnel,maintaining a reaction temperature ≦−5° C. The solution is allowed towarm to 20° C. and aged overnight at 20° C., until the amide is <0.5LCAP. The reaction is then cooled to −10° C. under nitrogen and isquenched slowly over 2 hours into 5N HCl (14 L) that is maintained at0-5° C. MTBE (12 L) is added and the biphasic mixture is agitated for 5min. After warming to 20°-25° C., it is allowed to settle for 30 min,and then the layers are separated. The organic layer is washed withwater twice (12 L).

The organic layer is vacuum transferred through a 1-micron in-line PTFEfilter into a distillation flask and is then concentrated to ˜12 L undervacuum (internal temperature <40° C.) to a minimum agitated volume. Thesolution is then azeotropically dried with toluene and taken to aminimum agitated volume again. The solution is used directly in the nextstep.

If a solid product is desired, heptane is added to the organic layerafter it has been concentrated to a minimum agitated volume. Thedistillation is continued under vacuum at 40°-55° C. until the finalvolume is 40 L. The solution is cooled to 35°-37° C., seeded (˜0.5%, 30gms) and then aged for 30 min to allow for a full seed bed to grow. Theslurry is cooled to 10° C. over 2-3 hrs. The slurry is then filtered,washed with 5° C. heptane (18 L), and allowed to dry fully on the filterpot using a vacuum/nitrogen sweep overnight. The dried solid is obtainedwith >99.9 ee %. The amide can be recrystallized from straight heptaneif the optical purity is not sufficient.

TFA (9 L) is added to a 100 L Buchi reactor under an inert atmosphereand is cooled to −5° C. The ketone product from Step 2 (5.50 kg, 13.1mol) is added as a solid followed by a TFA rinse (2 L). The solution iscooled to −5° C. and is stirred until all the solid dissolves. Thesilane (2.18 kg, 15.7 mol) is added slowly over ˜1 h (in two portions)while keeping the temperature at <0° C. The reaction is aged at −2 to−6° C. for 15-20 h, at which time LC reveals <2% of the ketone remains.A 50 w/w % KOH solution is prepared by adding 13.6 kg of KOH pellets (87w %) slowly to 10 L water while keeping the highly exothermicdissolution at <30° C. The solution is stored in a refrigerator.

The reaction is quenched with ˜2 L of the 50 w/w % KOH solution withvigorous stirring and cooling, keeping temp at ˜20° C. Cold THF (16.5 L,previously stored in freezer) is added, followed by slow addition of theremainder of the KOH solution (˜13.7 L), followed by a 2 L water rinsewhile keeping temp <20° C. After complete addition of KOH, the reactionis aged at room temperature. The reaction is quenched after 3 h with27.5 L IPAC and 20 L 20% w/v aq NaCl.

The aqueous and organic layers are separated. The organic layer iswashed with 26 L of 20% w/v aq NaCl, then with 36 L water, then with 31L 0.5 N HCl, and finally with 32 L of water. The organic layer isconcentrated to −10 L. Heptane (20 L) is added, yielding crystals. Theorganic layer is concentrated to ˜10 L. Heptane (20 L) is added again,and the organic layer is concentrated to ˜10 L. Heptane (22 L) is addedand the slurry is aged at rt. The solid is filtered and washed with 24 Lheptane. A solid product is obtained (98.8% purity, >99.95% ee, by LC).The solid is then re-dissolved in 12.5 L MeOH (endothermic). At rt, 3 Lwater is added, and the mixture is aged to initiate crystallization.Water (9.5 L) is added over ˜60 min at rt. After aging for 60 min, theslurry is filtered and the solid is washed with 5 L MeOH/water (1/1.5),5 L MeOH/water (1/4) and then 4 L water. The solid product is dried at50° C. under vacuum (99.9% pure by LC, >99.95% ee).

The reaction in Step 3 can also be carried out using Al(O-i-Pr)₃ as thereducing agent. For example, the ketone (6 kg) is heated at 50° C. with0.3 eq of Al(O-i-Pr)₃ (790 g) in 12 L IPA and 18 L of toluene for 15.5hours. The solution is cooled to ambient temperature, and solid KOHpellets (1.35 kg) are added slowly with vigorous stirring, while keepingthe temperature at <25° C. After about 2 hours, when HPLC shows >99.5%cyclization, 33 L of 1N HCl solution is added to quench the reaction,which is kept at <25° C. If a rag layer of solids forms, it should befiltered off to upgrade the enantiomeric excess. The organic layer isthen washed first with 36 L of 0.5N HCl, then with 6 L IPA combined with45 L water, and finally with 6 L IPA combined with 36 L water. Theorganic layer is transferred via an inline filter. The solvent isswitched to heptane (target volume is ˜42 L) at ˜40° C. until <2 v %toluene is left. Aging at rt for 2 h gives the solid product.

HPLC Method for assays used in Step 3:

Ace-C₈ column 250×4.6 mm A: MeCN; B: 0.1% H₃PO₄ in H₂O;

Gradient: 5A:95B at 0 min to 95A:5B at 9 min; hold 95A:5B until 13 min;return to 5A:95B 13-15 min.

Conditions: 35° C., 1.5 mL/min, 210 nm

Example 18

erythro-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Sodium bis(trimethylsilyl)amide (172 μL of a 1M solution in THF, 0.172mmol) was added to a stirred solution oferythro-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(50 mg, 0.129 mmol) in dry THF (1 mL) at room temperature under N₂. Thereaction was stirred for 15 min and a solution of2-(bromomethyl)-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl(27.0 mg, 0.0861 mmol) in dry THF (2 mL) was added by cannula. Thereaction was stirred at room temperature for 3 days. The reaction wasquenched with saturated NH₄Cl (10 mL) and extracted with EtOAc (3×20mL). The combined organic extracts were washed with brine (10 mL), dried(Na₂SO₄) and concentrated in vacuo to give the crude product. This waspurified by flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanesgradient) to afforderythro-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-oneas a colorless oil. R_(f)=0.64 (20% EtOAc/hexanes). LCMS calc.=620.18;found=620.2 (M+1)⁺. ¹H NMR (benzene-d₆, 600 MHz, 1:1 mixture ofatropisomers) δ 7.94 (s, 0.5H), 7.72 (s, 0.5H), 7.64 (s, 0.5H), 7.63 (s,0.5H), 7.39-7.34 (m, 3H), 7.12-7.04 (m, 2H), 6.95 (d, J=2.1 Hz, 0.5H),6.86 (d, J=1.7 Hz, 0.5H), 6.64 (d, J=8.5 Hz, 0.5H), 6.56 (d, J=8.5 Hz,0.5H), 4.99 (d, J=15.9 Hz, 0.5H), 4.93 (d, J=15.9 Hz, 0.5H), 4.73 (d,J=7.9 Hz, 0.5H), 4.61 (d, J=7.9 Hz, 0.5H), 3.88 (d, J=15.9 Hz, 0.5H),3.82 (d, J=15.9 Hz, 0.5H), 3.35 (s, 1.5H), 3.24 (s, 1.5H), 3.05 (septet,J=6.9 Hz, 0.5H), 3.01 (septet, J=6.9 Hz, 0.5H), 2.75 (m, 1H), 1.19 (dd,J=6.9, 2.7 Hz, 3H), 1.17 (dd, J=10.9, 6.9 Hz, 3H), −0.18 (d, J=6.4 Hz,1.5H), −0.33 (t, J=6.4 Hz, 1.5H). This compound was separated into itstwo enantiomers(4R,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-oneand(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-oneusing chiral HPLC (AD column, 20×250 mm, 3% i-PrOH in heptane).

Example 19

4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}imidazolidin-2-oneStep A:tert-butyl{2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-methyl}carbamate

To a solution of1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol(Example 6 Step B, 325.0 mg, 0.561 mmol) in CH₂Cl₂ (15 mL) was addedBOC₂O (122 mg, 0.561 mmol) and DIPEA (98 μL, 0.561 mmol). The reactionwas stirred at room temperature. After 5 hours, additional BOC₂O (50 mg,0.229 mmol) and DIPEA (50 μL, 0.287 mmol) were added. The reaction wasstirred at room temperature for 48 hours. The reaction was thenconcentrated to ˜2 mL, diluted with hexanes (8 mL) and purified by flashchromatography with 10 to 20% EtOAc/hexanes to affordtert-butyl{2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate.R_(f)=0.38 (25% EtOAc/hexanes). LCMS=580.3 (M+1−BOC)⁺. ¹H NMR (CD₂Cl₂,500 MHz) δ 7.78 (s, 1H), 7.54-7.67 (m, 4H), 7.23-7.33 (m, 2H), 6.90-6.95(m, 2H), 3.15-4.82 (m, 9H), 2.87 (m, 1H), 1.19-1.43 (m, 15H).

Step B:1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethylmethanesulfonate

To a solution oftert-butyl{2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate(350.1 mg, 0.516 mmol) in CH₂Cl₂ (15 mL) was added DIPEA (450 μL, 2.58mmol). The solution was cooled to 0° C. and MsCl (100 μL, 1.29 mmol) wasadded. After 45 minutes of stirring at 0° C., the reaction was dilutedwith EtOAc (100 mL) and washed with saturated NaHCO₃ (25 mL), brine (25mL), 1N HCl (25 mL), and brine (2×25 mL). The organic layer was driedover Na₂SO₄, filtered, and concentrated. The residue was put through ashort plug of silica gel with 25% EtOAc/hexanes and concentrated. Theproduct,1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethylmethanesulfonate, was used immediately in the next reaction withoutfurther characterization. R_(f)=0.33 (25% EtOAc/hexanes).

Step C: tert-butyl{2-azido-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate

The1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethylmethanesulfonate from the previous reaction was dissolved in DMPU (15mL) and treated with NaN₃ (140 mg, 2.15 mmol). The reaction was stirredat room temperature for 15 hours and then diluted with EtOAc (75 ml).The solution was washed with H₂O (5×40 mL) and brine (40 mL). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified with 20% EtOAc/hexanes to affordtert-butyl{2-azido-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate.R_(f)=0.52 (15% EtOAc/hexanes). LCMS=605.3 (M+1−BOC)⁺. ¹H NMR (C₆D₆, 500MHz, 70° C.) δ 7.80 (s, 1H), 7.67 (s, 1H), 7.48 (s, 2H), 7.36 (d, J=7.8Hz, 1H), 7.01-7.11 (m, 2H), 6.89 (m, 1H), 6.64 (d, J=8.6 Hz, 1H),4.22-4.69 (m, 3H), 3.28 (s, 3H), 2.61-3.16 (m, 3H), 1.34 (s, 9H),1.13-1.18 (m, 6H).

Step D: mixture of tert-butyl{2-amino-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamateand tert-butyl[1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl]carbamate

To a solution oftert-butyl{2-azido-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate(300 mg, 0.426 mmol) in EtOAc (15 mL) was added 10% Pd on C (100 mg).The reaction was placed under H₂ and stirred at room temperature for 5hours. At this time the reaction was complete to give a mixture of twoproducts, tert-butyl{2-amino-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamateand tert-butyl[1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl]carbamate.The catalyst was filtered off and the filtrate was concentrated toafford the product mixture. LCMS=679.3 (M+1)⁺. The products were used inthe next reaction without further purification or characterization.

Step E:1-[3,5-bis(trifluoromethyl)phenyl]-N²-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-methyl}ethane-1,2-diamine

To a solution of 283.5 mg (0.418 mmol) of the mixture of tert-butyl{2-amino-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamateand tert-butyl[1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl]carbamatein CH₂Cl₂ (15 mL) was added TFA (1.5 mL). The reaction was stirred atroom temperature for 5 hours and then poured into 1 N NaOH (50 mL). Themixture was extracted with CH₂Cl₂ (3×50 mL) and the organic extractswere combined, dried over Na₂SO₄, filtered, and concentrated.Purification of the residue by flash chromatography with 5 to 10%MeOH/CH₂Cl₂ gave1-[3,5-bis(trifluoromethyl)phenyl]-N²-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}ethane-1,2-diamine.R_(f)=0.46 (10% MeOH/CH₂Cl₂). LCMS=579.2 (M+1)⁺. ¹H NMR (CD₂Cl₂, 500MHz) δ 7.83 (s, 2H), 7.77 (s, 2H), 7.55 (d, J=7.8 Hz, 1H), 7.31 (d,J=8.1 Hz, 1H), 7.24 (dd, J=8.4, 2.3 Hz, 1H), 6.99 (d, J=2.0 Hz, 1H),6.92 (d, J=8.5 Hz, 1H), 4.06 (m, 1H), 3.59-3.76 (m, 2H), 3.69 (s, 3H),2.88 (m, 1H), 2.67 (dd, J=11.9, 4.3 Hz, 1H), 2.51 (m, 1H), 1.22 (d,J=6.9 Hz, 6H).

Step F:4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}imidazolidin-2-one

A solution of1-[3,5-bis(trifluoromethyl)phenyl]-N²-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}ethane-1,2-diamine(125.2 mg, 0.217 mmol) in CH₂Cl₂ (30 mL) was cooled to 0° C. and DIPEA(227 μL, 1.30 mmol) was added. Next, triphosgene (32.2 mg, 0.109 mmol)was added. The reaction was stirred at 0° C. for 45 minutes and thenpoured into saturated NaHCO₃ (20 mL). The mixture was extracted withEtOAc (100 mL) and the organic layer was washed with brine (25 mL),dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash chromatography with 40% EtOAc/hexanes to afford4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}imidazolidin-2-one.R_(f)=0.22 (40% EtOAc/hexane). LCMS=605.2 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) (atropisomers present in 1:1 ratio; doubling of some peaksobserved) δ 7.83 (s, 1H), 7.78 (s, 2H), 7.55-7.62 (m, 2H), 7.32 (d,J=7.8 Hz, 1H), 7.22 (m, 1H), 6.94 (s, 1H), 6.88 (d, J=8.3 Hz, 1H), 5.33& 5.24 (2 singlets, 1H), 4.80-4.88 (m, 1H), 4.00-4.61 (m, 2H), 3.72 &3.70 (2 singlets, 3H), 3.55-3.59 (m, 1H), 2.83-2.93 (m, 2H), 1.17-1.23(m, 6H).

The two enantiomers of this compound could be separated using an ADchiral column with 5% IPA/heptanes.

Example 20

(4R)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-phenylimidazolidin-2-oneStep A: tert-butyl [(1R)-2-hydroxy-1-phenylethyl]carbamate

To a solution of (2R)-2-amino-2-phenylethanol (400 mg, 2.91 mmol) inCH₂Cl₂ (15 mL) was added BOC₂O (636 mg, 2.91 mmol) and DIPEA (507 μL,2.91 mmol). The reaction was stirred at room temperature for 18 hours,diluted with EtOAc (75 mL) and washed with H₂O, brine, 1N HCl, brine,saturated NaHCO₃, and brine (25 mL each). The organic layer was driedover Na₂SO₄, filtered, and concentrated. Purification of the residue byflash chromatography with 50% EtOAc/hexanes afforded tert-butyl[(1R)-2-hydroxy-1-phenylethyl]carbamate. R_(f)=0.23 (40% EtOAc/hexane).¹H NMR (CDCl₃, 600 MHz) δ 7.27-7.37 (m, 5H), 5.27 (bs, 1H), 4.78 (bs,1H), 3.83 (bs, 2H), 2.46 (bs, 1H), 1.44 (bs, 9H).

Step B: tert-butyl [(1R)-2-oxo-1-phenylethyl]carbamate

To a solution of tert-butyl [(1R)-2-hydroxy-1-phenylethyl]carbamate (200mg, 0.844 mmol) in CH₂Cl₂ (20 mL) at 0° C. was added Dess-Martinperiodinane (447 mg, 1.05 mmol). The reaction was stirred at 0° C. for15 minutes and then at room temperature for 30 minutes. The reaction wasthen diluted with EtOAc (75 mL) and washed rapidly with 10% K₂CO₃ (2×30mL). The organic layer was dried over Na₂SO₄, filtered, andconcentrated. Purification of the residue on a short column of silicagel with 50% EtOAc/hexanes gave tert-butyl[(1R)-2-oxo-1-phenylethyl]carbamate. ¹H NMR (CDCl₃, 600 MHz) (a majorand a minor conformer observed). Data for major conformer given) δ 9.53(s, 1H), 7.29-740 (m, 5H), 5.80 (bs, 1H), 5.31 (m, 1H), 1.42 (s, 91-1).This material was used immediately in the following reaction.

Step C:tert-butyl[(1R)-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)-1-phenylethyl]carbamate

To a solution of tert-butyl[(1R)-2-oxo-1-phenylethyl]carbamate (113.8mg, 0.484 mmol) in MeOH (7 mL) was added1-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methenamine(98 mg, 0.303 mmol), followed by NaCNBH₃ (30 mg, 0.477 mmol) and HOAc (2drops). The reaction was stirred overnight at room temperature, dilutedwith EtOAc (75 mL), and washed with 1 N NaOH (25 mL) and brine (25 mL).The organic layer was dried over Na₂SO₄, filtered, and concentrated.Purification of the residue by flash chromatography with 5 to 25%EtOAc/hexanes gavetert-butyl[(1R)-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)-1-phenylethyl]carbamate.R_(f)=0.30 (25% EtOAc/hexane). LCMS=543.4 (M+1)⁺.

Step D:(1R)—N²-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1-phenylethane-1,2-diamine

To a solution oftert-butyl[(1R)-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)-1-phenylethyl]carbamate(150 mg, 0.277 mmol) containing minor impurities in CH₂Cl₂ (10 mL) wasadded TFA (1 mL). The reaction was stirred at room temperature for 2hours and then poured into 1 N NaOH (25 mL). The mixture was extractedwith CH₂Cl₂ (3×25 mL). The combined organic extracts were dried overNa₂SO₄, filtered, and concentrated. Purification of the resultingresidue by flash chromatography with 0 to 10% MeOH/CH₂Cl₂ afforded(1R)—N²-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1-phenylethane-1,2-diamine.R_(f)=0.27 (10% MeOH/CH₂Cl₂). LCMS=443.4 (M+1)⁺.

Step E:(4R)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-phenylimidazolidin-2-one

A solution of(1R)—N²-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1-phenylethane-1,2-diamine(96.0 mg, 0.22 mmol) in CH₂Cl₂ (15 mL) was cooled to 0° C. and DIPEA(230 μL, 1.32 mmol) was added followed by triphosgene (32.6 mg, 0.11mmol). After 45 minutes, the reaction was poured into saturated NaHCO₃(25 mL). The mixture was extracted with EtOAc (75 mL). The organic layerwas washed with brine, dried over Na₂SO₄, filtered, and concentrated.Purification of the residue by flash chromatography with 10 to 60%EtOAc/hexanes afforded(4R)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-phenylimidazolidin-2-one.The minor enantiomer was removed by chiral HPLC using an AD chiralcolumn and 15% IPA/heptanes to afford enantiomerically pure product.R_(f)=0.16 (40% EtOAc/hexanes). LCMS=469.3 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) (atropisomers present in 1:1 ratio, doubling of some peaksobserved) δ 7.65 (m, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.21-7.36 (m, 71-1),6.87-6.94 (m, 2H), 4.65-4.77 (m, 21-1), 4.10-4.49 (m, 2H), 3.71 & 3.72(2 singlets, 3H), 3.49-3.53 (m, 1H), 2.94-2.97 (m, 1H), 2.87 (m, 1H),1.19-1.24 (m, 6H).

Example 21

4-(4-chlorophenyl)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}imidazolidin-2-oneStep A:1-(4-chlorophenyl)-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol

A solution of1-[5′-isopropyl-2′-methoxy-5-(trifluoromethyl)biphenyl-2-yl]methanamine(300 mg, 1.1 mmol) and 2-(4-chlorophenyl)oxirane (143 μL, 1.2 mmol) inisopropyl alcohol (10.5 mL) was heated to reflux for 24 hours. Thereaction was concentrated and purified by flash chromatography with 5%to 80% EtOAc/hexanes to afford1-(4-chlorophenyl)-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol.R_(f)=0.37 (50% EtOAc/hexanes). LCMS=478.1 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.70 (s, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.33-7.19 (m, 6H), 6.97 (s,1H), 6.90 (d, J=8.5 Hz, 1H), 4.52 (m, 1H), 3.77-3.62 (m, 5H), 2.89 (m,1H), 2.71 (m, 1H), 2.51 (m, 1H), 1.24 (d, J=7.0 Hz, 6H).

Step B: benzyl[2-(4-chlorophenyl)-2-hydroxyethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate

To a solution of1-(4-chlorophenyl)-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol(40 mg, 0.08 mmol) in CH₂Cl₂ (2 mL) was added dibenzyl dicarbonate (24mg, 0.08 mmol). The reaction was stirred at room temperature for 24hours and then poured into H₂O (15 mL). The resultant mixture wasextracted with EtOAc (50 mL) and the organic layer was washed with brine(15 mL), dried over Na₂SO₄, filtered, and concentrated. Purification ofthe residue by flash chromatography with 5% to 60% EtOAc/hexanesafforded benzyl[2-(4-chlorophenyl)-2-hydroxyethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate.R_(f)=0.20 (25% EtOAc/hexanes). LCMS=612.2 (M+1)⁺. ¹H NMR(C₆D₆, 600 MHz,peaks broadened and/or doubled; rotamers and/or atropisomers present) δ7.98-6.45 (m, 15H), 5.00-3.46 (m, 6H), 3.20-2.96 (m, 5H), 2.72 (m, 1H),1.20-1.15 (m, 6H).

Step C: benzyl[2-azido-2-(4-chlorophenyl)ethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate

A solution of benzyl[2-(4-chlorophenyl)-2-hydroxyethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate.(44 mg, 0.07 mmol) in CH₂Cl₂ (6 mL) was cooled to 0° C. and N,Ndiisopropylethylamine (63 lit, 0.36 mmol) was added followed bymethanesulfonyl chloride (14 μL, 0.18 mmol). The reaction was stirred at0° C. for 30 minutes and then poured into saturated NaHCO₃ (15 mL). Theresultant mixture was extracted with EtOAc (50 mL) and the organic layerwas washed with brine (15 mL), dried over Na₂SO₄, filtered through ashort plug of silica gel, and concentrated. The residue was redissolvedin DMPU (6 mL) and sodium azide (12 mg, 0.18 mmol) was added. Thereaction was stirred at room temperature for 24 hours and then pouredinto H₂O (15 mL). The resultant mixture was extracted with EtOAc (50 mL)and the organic layer was washed with H₂O (2×15 mL) and brine (15 mL),dried over Na₂SO₄, filtered, and concentrated. Purification of theresidue by flash chromatography with 25% EtOAc/hexanes afforded benzyl[2-azido-2-(4-chlorophenyl)ethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate.R_(f)=0.66 (25% EtOAc/hexanes). LCMS=637.3 (M+1)⁺. ¹H NMR (C₆D₆, 600MHz, peaks doubled; rotamers and/or atropisomers present) δ 8.03-6.52(m, 15H), 5.00-5.08 (m, 2H), 4.76-4.12 (m, 3H), 3.28-2.86 (m, 5H), 2.77(m, 1H), 1.23-1.18 (m, 6H).

Step D: benzyl[2-amino-2-(4-chlorophenyl)ethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate

To a solution of benzyl[2-azido-2-(4-chlorophenyl)ethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate(30 mg, 0.05 mmol) in THF (1 mL) was added PtO₂ (8 mg) and the reactionwas stirred at room temperature under hydrogen for 1 hour. The catalystwas removed by filtration through a plug of Celite with 100% EtOAc andthe filtrate was concentrated to afford crude benzyl[2-amino-2-(4-chlorophenyl)ethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate.R_(f)=0.66 (25% EtOAc/hexanes). LCMS=611.3 (M+1)⁺.

Step E:4-(4-chlorophenyl)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}imidazolidin-2-one

To a solution of benzyl[2-amino-2-(4-chlorophenyl)ethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate(30 mg, 0.05 mmol) in THF (2 mL) was added potassiumbis(trimethylsilyl)amide (295 μL of a 0.5M solution in toluene, 0.147mmol) The reaction was stirred at room temperature for 30 minutes andthen quenched with saturated NH₄Cl (15 mL). The resultant mixture wasextracted with EtOAc (25 mL) and the organic layer was washed with H₂O(15 mL) and brine (15 mL), dried over Na₂SO₄, filtered, andconcentrated. Purification of the residue by flash chromatography with5% to 60% EtOAc/hexanes afforded4-(4-chlorophenyl)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}imidazolidin-2-one.R_(f)=0.46 (5% MeOH/CH₂Cl₂). LCMS=503.1 (M+1)⁺. ¹H NMR (C₆D₆, 600 MHz,atropisomers observed; doubling of peaks.) δ 7.90-7.03 (m, 6H),6.89-6.20 (m, 4H), 4.69-3.88 (m, 3H), 3.16 (s, 3H), 2.88-2.30 (m, 3H),1.18-1.13 (m, 6H).

Example 22

(4R)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-3-methyl-4-phenylimidazolidin-2-one

To a solution of(4R)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-phenylimidazolidin-2-one(12.6 mg, 0.0269 mmol) in THF (1.5 mL) was added MeI (10 μL, 0.162mmol), followed by KHMDS (162 μL of a 0.5 M solution in toluene, 0.081mmol). The reaction was stirred at room temperature for 10 minutes, andthen poured into water (10 mL). The mixture was extracted with EtOAc (30mL) and the organic layer was washed with brine (10 mL), dried overNa₂SO₄, filtered, and concentrated. Purification of the residue by flashchromatography with 50% EtOAc/hexanes afforded(4R)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-3-methyl-4-phenylimidazolidin-2-one.R_(f)=0.26 (40% EtOAc/hexanes). LCMS=483.2 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz, atropisomers observed; doubling of peaks.) δ 7.68-7.53 (m, 2H),7.21-7.36 (m, 7H), 6.87-6.94 (m, 2H), 4.08-4.56 (m, 3H), 3.72 & 3.71 (2singlets, 3H), 3.34-3.38 (m, 1H), 2.77-2.89 (m, 2H), 2.67 & 2.63 (2singlets, 3H), 1.18-1.26 (m, 6H).

Following the procedures outlined in EXAMPLES 1-22 the compounds listedin Table 1 were prepared:

TABLE 1

LCMS Example R (M + 1)⁺ 23

618.1 24

470.2 25

470.4 26

538.2 27

504.1 28

538.2 29

471.2 30

538.2 31

504.2 32

476.2 33

471.2 34

484.2 35

484.2 36

620.2 37

620.2 38

470.2 39

469.2 40

475.2 41

503.1 42

503.1 43

537.2 44

537.2 45

470.2 46

470.2 47

619.2 48

634.1 49

634.1

Example 50

4-[3,5-bis(trifluoromethyl)phenyl]-2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,2,5-thiadiazolidine1,1-dioxide

A solution of1-[3,5-bis(trifluoromethyl)phenyl]-N²-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}ethane-1,2-diamine(8.0 mg, 0.014 mmol) and sulfamide (2.0 mg, 0.021 mmol) in pyridine (300μL) was heated to 120° C. in a sealed tube. After 3 hours, the reactionwas cooled to room temperature and diluted with 25 mL of EtOAc. Theorganic solution was washed with 1 N HCl (2×5 mL) and brine (1×5 mL),dried over Na₂SO₄, filtered, and concentrated. Purification of theresidue by PTLC with 25% EtOAc/hexanes afforded4-[3,5-bis(trifluoromethyl)phenyl]-2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,2,5-thiadiazolidine1,1-dioxide. R_(f)=0.29 (25% EtOAc/hexanes). LCMS=641.1 (M+1)⁺. ¹H NMR(CDCl₃, 500 MHz; atropisomers present) δ 7.58-7.85 (m, 5H), 7.35-6.86(m, 4H), 4.82-4.94 (m, 2H), 3.54-4.42 (m, 6H), 2.71-2.91 (m, 2H),1.11-1.26 (m, 6H).

Example 51

5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-oneStep A:[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol

To a solution of 1.08 g of5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile(EXAMPLE 3) in 25 mL of n-PrOH, was added 0.97 g of KOH. The mixture washeated to reflux and stirred at this temperature for 36 h, then cooledand concentrated to a clear oil. This oil was partitioned between 15 mLof water and 10 mL of Et₂O. The aqueous phase was extracted with 10 mLof Et₂O. The combined organics were washed with brine (15 mL), driedover Na₂SO₄, and concentrated. The residue was purified by flashchromatography on a Biotage Horizon 40S column, eluting with 1 CV of 95%hexanes-5% of a mixture of 5% formic acid in acetone, followed by alinear gradient of the acetone mixture in hexanes from 5 to 100% over 10CV. The resulting white solid was dissolved in 10 mL of 9:1 benzene-MeOHand excess TMSCH₂N₂ was added. The mixture was stirred for 10 min atroom temperature, then quenched with trifluoroacetic acid andconcentrated. The residue was dissolved in 15 mL of Et₂O and cooled to0° C. A 1-M solution of LiAlH₄ in Et₂O (5.4 mL) was added dropwise viaaddition funnel. The cooling bath was removed once the addition wascomplete, and the mixture was stirred 2 h at room temperature, thenrecooled to 0° C. and quenched by dropwise addition of 0.2 mL of water,0.2 mL of 15% aqueous NaOH, and 0.5 mL of water. The cooling bath wasremoved once the addition was complete, and the mixture was stirred 30min at room temperature, filtered (washing the solids liberally withEt₂O), and concentrated. Flash chromatography on a Biotage Horizon, 40Scolumn, eluting with 1 CV of 4% EtOAc in hexanes, followed by a lineargradient of EtOAc in hexanes from 4 to 100% over 10 CV provided thetitle compound. Mass spectrum (ESI) 307.2 (M−17). ¹H NMR (500 MHz,CDCl₃): δ 7.85 (s, 1H), 7.60 (d, J=8 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.25(dd, J=2 Hz, 9 Hz, 1H), 6.99 (d, J=2.5 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H),4.49 (m, 2H), 3.74 (s, 3H), 2.90 (septet, J=7 Hz, 1H), 1.25 (d, J=7 Hz,6H).

Step B:5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde

To a solution of 0.725 g of[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol in 10mL of CH₂Cl₂ was added 1.14 g of Dess-Martin periodinane. The mixturewas stirred at room temperature for 30 min, then filtered andconcentrated. The residue was purified by flash chromatography on aBiotage Horizon, 40S column, eluting with 1 CV of 1% EtOAc in hexanes,followed by a linear gradient of EtOAc in hexanes from 1 to 100% over 10CV to provide the title compound. Mass spectrum (ESI) 323.2 (M+1). ¹HNMR (500 MHz, CDCl₃): δ 9.81 (s, 1H), 8.28 (s, 1H), 7.88 (dd, J=1.5 Hz,8 Hz, 1H), 7.54 (d, J=8 Hz, 1H), 7.33 (dd, J=2 Hz, 8 Hz, 1H), 7.16 (d,J=2.5 Hz, 1H), 6.95 (d, J=8.5 Hz, 1H), 3.74 (s, 3H), 2.95 (septet, J=7Hz, 1H), 1.29 (d, J=7 Hz, 6H).

Step C:2-amino-1-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]ethanol

To a solution of 0.679 g of5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde in1.5 mL of CH₂Cl₂ was added ca. 5 mg of ZnI₂, then 0.23 g oftrimethylsilyl cyanide. The mixture was stirred at room temperature for3 h, and then partitioned between 15 mL of water and 10 mL of Et₂O. Theaqueous phase was extracted with 2×10 mL of Et₂O. The combined organicswere dried over Na₂SO₄ and concentrated. The residue was dissolved in 15mL of Et₂O and cooled to 0° C. A 1-M solution of LiAlH₄ in Et₂O (4.2 mL)was added dropwise via addition funnel. The cooling bath was removedonce the addition was complete, and the mixture was stirred overnight atroom temperature, then recooled to 0° C. and quenched by dropwiseaddition of 0.15 mL of water, 0.15 mL of 15% aqueous NaOH, and 0.4 mL ofwater. The cooling bath was removed once the addition was complete, andthe mixture was stirred 30 min at room temperature, filtered (washingthe solids liberally with Et₂O), and concentrated to provide the titlecompound, which was used without further purification. Mass spectrum(ESI) 354.2 (M+1). Some ¹H NMR signals are doubled because ofatropoisomerism. ¹H NMR (500 MHz, CDCl₃): δ 7.88 (s, 1H), 7.55 (app t,J=7.5 Hz, 1H), 7.22-7.28 (m, 2H), 6.99, 6.95 (d, J=2.5 Hz, 1H), 6.92,6.90 (sm 1H), 4.52 (m, 1H), 3.70 (s, 3H), 2.90 (septet, J=7 Hz, 1H),2.81 (m, 1H), 2.60-2.70 (m, 2H), 1.23-1.28 (m, 6H).

Step D:5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one

To a 0° C. solution of 0.44 g of2-amino-1-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]ethanolin 15 mL of CH₂Cl₂ was added 0.241 g of diisopropylethylamine, then0.185 g of triphosgene. The mixture was stirred at 0° C. for 30 min, andthen diluted with 30 mL of EtOAc and 20 mL of saturated NaHCO₃. Thephases were separated and the organic phase was washed with 20 mL ofbrine, dried (Na₂SO₄), and concentrated. The residue was purified byflash chromatography on a Biotage Horizon, 40S column, eluting with 1 CVof 5% EtOAc in hexanes, followed by a linear gradient of EtOAc inhexanes from 5 to 100% over 10 CV to provide the title compound. Massspectrum (ESI) 380.2 (M+1). ¹H NMR signals are doubled because ofatropoisomerism ¹H NMR (500 MHz, CDCl₃): δ 7.90, 7.86 (s, 1H), 7.66 (d,J=8 Hz, 1H), 7.35 (d, J=8 Hz, 1H), 7.27 (dd, J=2.5 Hz, 8.5 Hz 1H), 7.03(d, J=2.5 Hz, 0.5H), 6.87-6.93 (m, 1.5H), 5.65, 5.50 (t, J=8 Hz, 1H),5.23, 5.09 (s, 1H), 3.75 (s, 1.5H), 3.69 (s, 1.5H), 3.68, 3.51 (t, J=9Hz, 1H), 3.31, 3.19 (t, J=8.5 Hz, 0.5H), 2.90 (septet, J=7 Hz, 1H),1.25, 1.24 (d, J=7 Hz, 6H).

Further purification by HPLC on Chiralpak AD 2×25 cm, eluting with 10%isopropanol in heptane at 9 mL/min, provided two enantiomers: enantiomerA, t_(R)=15.1 min; enantiomer B, t_(R)=17.4 min.

Example 52

3-Benzyl-5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one

To a 0° C. solution of 44 mg of5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-onein 1 mL of DMF was added 10 mg of sodium hydride. The mixture wasstirred 10 min at room temperature, and then 24 mg of benzyl bromide wasadded. The mixture was stirred overnight at room temperature, thendiluted with 15 mL of EtOAc and 5 mL of water. The phases were separatedand the organic phase was washed with 5 mL each of water and brine,dried (Na₂SO₄), and concentrated. The residue was purified by flashchromatography on a Biotage Horizon, 25S column, eluting with 1 CV ofhexanes, followed by a linear gradient of EtOAc in hexanes from 0 to 50%over 10 CV to provide the title compound. Mass spectrum (ESI) 470.1(M+1). ¹H NMR (500 MHz, CDCl₃): δ 7.86, 7.76 (s, 1H), 7.62 (d, J=8 Hz,1H), 7.14-7.40 (m, 7H), 7.01, 6.77 (d, J=2.5 Hz, 1H), 6.87, 6.83 (d,J=8.5 Hz, 1H), 5.45, 5.53 (m, 1H), 4.30-4.53 (m, 2H), 3.73, 3.55 (s,3H), 3.48, 3.30 (m, 1H), 3.10, 2.96 (t, J=8.5 Hz, 1H), 2.89, 2.82(septet, J=7 Hz, 1H), 1.24, 1.16 (m, 6H).

Example 53

3-[3,5-bis(trifluoromethyl)benzyl]-5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one(racemic)

Following the procedure described in EXAMPLE 50, 43 mg of5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-oneand 43 mg of 3,5-bis(trifluoromethyl)benzyl bromide gave the titlecompound. Mass spectrum (ESI) 606.1 (M+1). ¹H NMR signals are doubledbecause of atropoisomerism. ¹H NMR (500 MHz, CDCl₃): δ 7.58-7.88 (m,5H), 7.34 (d, J=8 Hz, 1H), 7.23 (m, 1H), 7.02, 6.79 (d, J=2 Hz, 1H),6.88, 6.85 (d, J=8.5 Hz, 1H), 5.45, 5.42 (m, 1H), 4.52-4.64 (m, 1.5H),4.36 (d, J=15.5 Hz, 0.5H), 3.74, 3.57 (s, 3H), 3.49, 3.34 (m, 1H), 3.09,2.99 (t, J˜8.5 Hz, 1H), 2.89, 2.81 (septet, J=7 Hz, 1H), 1.24, 1.12 (m,6H).

Example 54

3-[3,5-bis(trifluoromethyl)benzyl]-5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one(enantiomer A)

Following the procedure described in EXAMPLE 50, 43 mg of5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one,enantiomer A, and 43 mg of 3,5-bis(trifluoromethyl)benzyl bromide gavethe title compound. Analytical HPLC on Chiralpak AS 4.6×250 mm, elutingwith 5% isopropanol in heptane at 0.5 mL/min: t_(R)=9.9 min

Example 55

3-[3,5-bis(trifluoromethyl)benzyl]-5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one(enantiomer B)

Following the procedure described in EXAMPLE 50, 44 mg of5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one,enantiomer B, and 43 mg of 3,5-bis(trifluoromethyl)benzyl bromide gavethe title compound. Analytical HPLC on Chiralpak AS 4.6×250 mm, elutingwith 5% isopropanol in heptane at 0.5 mL/min: t_(R)=11.0 min

Example 56

1-(4-Fluorophenyl)-1-hydroxyacetone

A suspension of ground LaCl₃ (26 mg, 0.104 mmol) in dry THF (7.8 mL)under N₂ was cooled to −78° C. and stirred for 15 min. A solution ofn-BuLi (1.6 M in hexanes, 195 μL, 0.312 mmol) was added and stirring wascontinued for 15 min. The reaction was warmed to 0° C. and stirred for30 min. Trimethylsilyl cyanide (31 mg, 42 μL, 0.312 mmol) was added andthe reaction was stirred for 30 min at 0° C. and warmed to roomtemperature over 30 min. A solution of acetyltrimethylsilane (Cunico, R.F., Kuan, C.-P., J. Org. Chem., 1985, 50, 5410-5413) (121 mg, 1.04 mmol)and 4-fluorobenzaldehyde (142 mg, 1.14 mmol) in dry THF (19 mL) wasadded by cannula and the reaction was stirred at room temperature for 2h. After this time 1N HCl (24 mL) was added and the reaction was stirredfor 1 h. Et₂O (25 mL) was added and the organic layer was separated andwashed with H₂O (2×25 mL). The combined aqueous layers were extractedwith Et₂O (3×50 mL). The combined organic extracts were dried (MgSO₄)and concentrated in vacuo to give the crude product. This was purifiedby flash chromatography (Si, 25×160 mm, 0-50% EtOAc in hexanes gradient)to give 1-(4-fluorophenyl)-1-hydroxyacetone as a colorless solid.R_(f)=0.31 (20% EtOAc/hexanes). ¹H NMR (CDCl₃, 500 MHz) δ 7.29 (m, 2H),7.08-7.04 (m, 2H), 5.06 (d, J=3.6 Hz, 1H), 4.35 (t, J=6.5 Hz, 1H), 2.05(s, 3H).

Example 57

erythro- andthreo-1-(4-Fluorophenyl)-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propan-1-ol

NaCNBH₃ (19 mg, 0.306 mmol) was added to a solution of{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amine(67 mg, 0.204 mmol) and 1-(3,5-dichlorophenyl)-1-hydroxyacetone (45 mg,0.204 mmol) in MeOH at room temperature followed by acetic acid (2drops). The reaction was stirred for 5 h at room temperature. Thereaction mixture was diluted with EtOAc (20 mL), H₂O (20 mL and brine (5mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combinedorganic extracts were dried (Na₂SO₄) and concentrated in vacuo to givethe crude product. This was purified by flash chromatography (Si, 12×160mm, 0-50% EtOAc in hexanes gradient) to give the two possiblediastereoisomers,erythro-1-(4-fluorophenyl)-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propan-1-ol(68.4 mg) andthreo-1-(4-fluorophenyl)-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propan-1-ol(48.9 mg) as colorless oils. erythro-diastereoisomer: R_(f)=0.40 (20%EtOAc/hexanes). LCMS calc.=476.22; found=476.2 (M+1)⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.72 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.36 (m, 1H), 7.27 (dd,J=8.5, 2.3 Hz, 1H), 7.19 (m, 2H), 7.04-6.92 (m, 4H), 4.63-4.56 (m, 1H),3.85-3.65 (m, 7H), 2.92 (m, 1H), 2.72 (m, 1H), 1.26 (t, J=8.0 Hz, 6H),0.64 (t, J=5.4 Hz, 3H). threo-diastereoisomer: R_(f)=0.20 (20%EtOAc/hexanes). LCMS calc.=476.22; found=476.2 (M+1)⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.73 (d, J=9.0 Hz, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.32 (m, 1H),7.24 (m, 3H), 7.07-6.97 (m, 3H), 6.92 (d, J=8.5 Hz, 1H), 4.05 (d, J=7.9Hz, 1H), 3.82-3.70 (m, 5H), 3.59 (d, J=13 Hz, 1H), 3.51 (d, J=13 Hz,1H), 2.90 (m, 1H), 2.51 (m, 1H), 1.25 (m, 6H), 0.73 (d, J=6.4 Hz, 3H).

Example 58

erythro-5-(4-Fluorophenyl)-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

As for EXAMPLE 7 Step 3. R_(f)=0.38 (20% EtOAc/hexanes). LCMScalc.=502.20; found=502.2 (M+1)⁺. ¹H NMR (500 MHz, benzene-d₆, 1:1mixture of atropisomers) δ 7.96 (s, 0.5H), 7.75 (s, 0.5H), 7.35 (d,J=7.7 Hz, 1H), 7.10-7.06 (m, 2H), 6.94 (d, J=2.1 Hz, 0.5H), 6.88 (d,J=2.1 Hz, 0.5H), 6.69-6.62 (m, 4.5H), 6.55 (d, J=8.4 Hz, 0.5H), 4.95 (d,J=15.9 Hz, 0.5H), 4.86 (d, J=15.8 Hz, 0.5H), 4.80 (d, J=7.9 Hz, 0.5H),4.70 (d, J=7.8 Hz, 0.5H), 4.04 (d, J=15.8 Hz, 0.5H), 3.93 (d, J=15.9 Hz,0.5H), 3.36 (s, 1.5H), 3.22 (s, 1.5H), 3.14 (m, 0.5H), 3.05 (m, 0.5H),2.79-2.71 (m, 1H), 1.18 (m, 6H), 0.02 (d, J=6.5 Hz, 1.5H), −0.04 (d,J=6.5 Hz, 1.5H). This compound was separated into its two enantiomers(4R,5S)-5-(4-Fluorophenyl)-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-oneand(4S,5R)-5-(4-Fluorophenyl)-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-oneusing chiral HPLC (AD column, 20×250 mm, 3% EtOH in heptane).

Following the procedures outlined in EXAMPLE 58 the compounds listed inTable 2 were prepared:

TABLE 2

LCMS Example R (M + 1)⁺ 59

502.2 60

502.2 61

552.2 62

552.2 63

552.1

Example 64

1-{[5′-Isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-phenylpyrrolidin-2-one

Sodium bis(trimethylsilyl)amide (114 μL of a 1M solution in THF, 0.114mmol) was added to a stirred solution of 4-phenylpyrrolidin-2-one(Winans, C. F., Adkins, H., J. Am. Chem. Soc., 1933, 55, 4167-4176) (17mg, 0.103 mmol) in dry THF (1 mL) at room temperature under N₂. Thereaction was stirred for 5 min and a solution of2-(bromomethyl)-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl (20mg, 0.0516 mmol) in dry THF (2 mL) was added by cannula. The reactionwas stirred at room temperature for 3 days. The reaction was quenchedwith saturated NH₄Cl (10 mL) and extracted with EtOAc (3×20 mL). Thecombined organic extracts were washed with brine (10 mL), dried (Na₂SO₄)and concentrated in vacuo to give the crude product. This was purifiedby flash chromatography (Si, 12×160 mm, 0-90% EtOAc in hexanes gradient)to afford1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-phenylpyrrolidin-2-oneas a colorless oil. R_(f)=0.11 (20% EtOAc/hexanes). LCMS calc.=468.22;found=468.2 (M+1)⁺. ¹H NMR (600 MHz, benzene-d₆, 1:1 mixture ofatropisomers) δ 7.79 (s, 0.5H), 7.73 (s, 0.5H), 7.33 (d, J=7.7 Hz, 1H),7.08-7.04 (m, 4H), 6.99 (m, 1H), 6.92 (s, 0.5H), 6.88 (s, 0.5H), 6.76(dd, J=16.0, 7.4 Hz, 2H), 6.60 (dd, J=8.5, 3.1 Hz, 1H), 4.58 (d, J=15.4Hz, 1H), 4.38 (t, J=13.9 Hz, 1H), 3.29 (s, 1.5H), 3.26 (s, 1.5H),2.85-2.73 (m, 3H), 2.63-2.57 (m, 1H), 2.38-2.28 (m, 1H), 2.21-2.11 (m,1H), 1.20-1.16 (m, 6H).

Example 65

4-(3,4-Difluorophenyl)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}pyrrolidin-2-one

Prepared by a similar method as EXAMPLE 64 starting with4-(3,4-difluorophenyl)pyrrolidin-2-one (prepared by a similar method asin Marivet, M. C., Bourguignon, J.-J.; Lugnier, C., Mann, A., Stoclet,J.-C., Wermuth, C.-G. J. Med. Chem., 1989, 32, 1450-1457). LCMScalc.=504.20; found=504.2 (M+1)⁺.

Example 66

5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]1,3-oxazolidin-2-one

A stirred suspension of sodium hydride (60% in oil, 167 mg, 4.18 mmol)in THF (5 mL) was treated at 0° C. with5-[3,5-bis(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one (500 mg, 1.67mmol) dissolved in THF (1 mL), under an atmosphere of N₂. The reactionwas stirred for 20 min and a solution of2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (610 mg, 1.67 mmol) inTHF (1 mL) was added dropwise. The reaction was stirred at roomtemperature for 18 h. The reaction was quenched with H₂O (1 mL) andpartitioned between EtOAc (80 mL) and H₂O (25 mL). The aqueous phase wasre-extracted with EtOAc (2×20 mL) and the combined organic extracts werewashed with brine (30 mL), dried (MgSO₄) and concentrated in vacuo togive the crude product. This was purified by flash silica-gelchromatography (0-30% EtOAc in hexanes gradient) to afford5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]1,3-oxazolidin-2-one.R_(f)=0.55 (515% EtOAc/hexanes). LCMS 584 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 8.05 (d, J=8.2 Hz, 1H), 7.95 (br s, 1H), 7.85 (br s, 2H), 7.51(br s, 1H), 7.32 (m, 1H), 5.72 (t, J=8.0 Hz, 1H), 4.74 (d, J=15.5 Hz,1H), 4.64 (d, J=15.3 Hz), 4.14 (t, J=7.1 Hz, 1H), 3.47 (dd, J=7.1, 1.6Hz).

Example 67

(4S)-4-benzyl-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-methyl}-1,3-oxazolidin-2-oneStep A:(4S)-4-benzyl-3-[2-iodo-5-(trifluoromethyl)benzyl]1,3-oxazolidin-2-one

A stirred suspension of sodium hydride (60% in oil, 27 mg, 0.68 mmol) inTHF (3 mL) was treated at 0° C. with (S)-4-benzyl-2-oxazolidinone (49mg, 0.27 mmol) dissolved in THF (1 mL), under an atmosphere of N₂. Thereaction was stirred for 20 min and a solution of2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (100 mg, 0.27 mmol) inTHF (1 mL) was added dropwise. The reaction was stirred at roomtemperature for 18 h. The reaction was quenched with H₂O (1 mL) andpartitioned between EtOAc (80 mL) and H₂O (25 mL). The aqueous phase wasre-extracted with EtOAc (2×20 mL) and the combined organic extracts werewashed with brine (30 mL), dried (MgSO₄) and concentrated in vacuo togive the crude product. This was purified by flash silica-gelchromatography (0-30% EtOAc in hexanes gradient) to afford(4S)-4-benzyl-3-[2-iodo-5-(trifluoromethyl)benzyl]1,3-oxazolidin-2-one.R_(f)=0.45 (15% EtOAc/hexanes). LCMS 462 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz)δ 8.04 (d, J=8.2 Hz, 1H), 7.54 (br s, 1H), 7.33-7.27 (m, 5H), 7.11-7.10(m, 2H), 7.32 (m, 1H), 4.80 (d, J=16.0 Hz, 1H), 4.49 (d, J=16.1 Hz),4.28 (t, J=8.7 Hz, 1H), 4.25 (t, J=9.1, 4.8 Hz, 1H), 3.94 (m, 1H), 3.16(dd, J=13.5, 4.8 Hz, 1H), 2.73 (dd, J=9.1, 4.4 Hz, 1H).

Step B:(4S)-4-benzyl-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one

A stirred suspension of(4S)-4-benzyl-3-[2-iodo-5-(trifluoromethyl)benzyl]1,3-oxazolidin-2-one(63 mg, 0.137 mmol), 2-methoxy-5-isopropylphenyl boronic acid (52 mg,0.274 mmol), K₂CO₃ (47 mg, 0.34 mmol) and Pd(OAc)₂ (9.2 mg, 0.0137 mmol)in acetone:H₂O (5:1) (6 mL) was heated at reflux for 1 h. The reactionmixture was concentrated in vacuo, diluted with H₂O (15 mL) andextracted with EtOAC (3×30 mL). The combined organic extracts werewashed with brine (30 mL), dried (MgSO₄), filtered and concentrated. Thecrude product was purified by silica-gel flash chromatography (0-20%EtOAc in hexanes gradient) to(4S)-4-benzyl-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one.R_(f)=0.35 (15% EtOAc/hexanes). LCMS 484 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz)(atropisomers present; doubling of some peaks observed in ¹H NMR) δ 7.72(br s 1H), 7.65 (br s, 1H), 7.42 (m, 1H), 7.32-7.22 (m, 3H), 7.08 (d,J=2.3 Hz, 1H), 6.90-6.84 (m, 3H), 4.80 (d, J=15.8 Hz, 1H), 4.35 (d,J=15.8 Hz), 4.28 (t, J=8.7 Hz, 1H), 3.96-3.92 (m, 3H), 3.78 (s, 3H),3.62-3.52 (m, 1H), 2.94-2.86 (m, 1H), 2.82 (dd, J=9.4, 3.9 Hz, 1H), 2.42(dd, J=9.6, 3.9 Hz), 1.26 (s, 3H), 1.10 (s, 3H).

Example 68

2-Iodo-5-(trifluoromethyl)benzoic acid

Potassium hydroxide (3.78 g; 0.0673 mol) was added to a stirred solutionof 2-iodo-5-(trifluoromethyl)benzonitrile (EXAMPLE 2; 4 g; 0.0135 mol)in a 1:1 isopropanol:H₂O solution (60 mL). The reaction was heated atreflux for 14 h and then partitioned between H₂O (50 mL) and EtOAc (50mL). The aqueous layer was extracted with EtOAc (50 mL) and acidified topH 5 with 6N HCl. The aqueous layer was further extracted with EtOAc(4×50 mL) and the combined extracts were washed with brine (50 mL),dried over MgSO₄, filtered, and concentrated in vacuo to afford2-iodo-5-(trifluoromethyl)benzoic acid as a yellow solid. LCMS=317.0(M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 8.27 (d, J=1.6 Hz, 1H), 8.25 (d,J=8.2 Hz, 1H), 7.47 (dd, J=8.2, 1.8 Hz, 1H).

Example 69

[2-Iodo-5-(trifluoromethyl)phenyl]methanol

Borane-THF (1.0M solution in THF; 94 mL; 94 mmol) was added to a stirredsolution of 2-iodo-5-(trifluoromethyl)benzoic acid (2.97 g; 9.4 mmol) inTHF (300 mL) at 0° C. under N₂. The reaction was heated at reflux for 90min and then carefully quenched with 6N HCl until no further gasevolution. The reaction was diluted with H₂O (250 mL) and extracted withEtOAc (3×250 mL). The combined extracts were washed with brine (300 mL),dried over MgSO₄, filtered, and concentrated in vacuo. The crudematerial was purified by flash chromatography (0-25% EtOAc/hexanesgradient) to afford [2-iodo-5-(trifluoromethyl)phenyl]methanol as awhite solid. LCMS=285.0 (M−17)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 7.97 (d,J=8.3 Hz, 1H), 7.79 (s, 1H), 7.28 (d, J=8.4 Hz, 1H), 4.75 (s, 2H). Analternative procedure is as follows: To a solution of2-Iodo-5-(trifluoromethyl)benzaldehyde (EXAMPLE 80, Step A, 9 g) in THF(100 mL) and water (10 mL) at 0° C. was added NaBH₄ (0.5 g). Thereaction was stirred 30 minutes. To the reaction mixture was addeddilute aqueous HCl (cautiously). The mixture was extracted with etherand the ether layer was washed with water, then brine. The ether layerwas then dried over anhydrous MgSO₄, filtered and concentrated. Thematerial is chromatographed on SiO₂ using a step gradient of 1:3CH₂Cl₂/hexanes, then 1:1 CH₂Cl₂/hexanes, then 100% CH₂Cl₂ to afford[2-iodo-5-(trifluoromethyl)phenyl]methanol as a white solid.

Example 70

2-(Bromoethyl)-1-iodo-4-(trifluoromethyl)benzene

Carbon tetrabromide (1.86 g; 5.6 mmol) and triphenylphosphine (1.47 g;5.6 mmol) were added successively to a stirred solution of[2-iodo-5-(trifluoromethyl)phenyl]methanol (1.13 g; 3.74 mmol) in CH₂Cl₂(25 mL) at 0° C. under N₂. The reaction was stirred at room temperaturefor 48 h. A second equivalent of carbon tetrabromide (1.2 g; 3.74 mmol)and triphenylphosphine (0.98 g; 3.74 mmol) was added and the reactionwas stirred an additional 14 h. The solvent was removed in vacuo and theresidue was purified by flash chromatography (0-25% EtOAc/hexanesgradient) to afford 2-(bromoethyl)-1-iodo-4-(trifluoromethyl)benzene asa clear oil. ¹H NMR (CDCl₃, 500 MHz): δ 8.02 (d, J=8.2 Hz, 1H), 7.73 (d,J=1.8 Hz, 1H), 7.26 (dd, J=8.3, 1.8 Hz, 1H), 4.64 (s, 2H).

Example 71

5-[3,5-bis(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one

Following the procedure described in EXAMPLE 13, 5.46 g of2-amino-1-[3,5-bis(trifluoromethyl)phenyl]ethanol yielded5-[3,5-bis(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one as an off-whitesolid. LCMS=300.1 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 7.94 (s, 1H), 7.89(s, 2H), 5.81-5.77 (m, 1H), 5.29 (s, 1H), 4.17-4.12 (m, 1H), 3.59-3.55(m, 1H).

Example 72

5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one

A mixture of5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one(60 mg; 0.103 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid(27 mg; 0.129 mmol), palladium acetate (7 mg; 0.0103 mmol), andpotassium carbonate (36 mg; 0.257 mmol) in 5:1 acetone/water (6 mL) washeated at reflux for 1 h. Acetone was removed in vacuo and the residuewas diluted with H₂O (10 mL) and extracted with CH₂Cl₂ (3×10 mL). Thecombined extracts were washed with brine (10 mL), dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by flashchromatography (0-25% EtOAc/hexanes gradient) to afford5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-oneas a clear glass. LCMS=624.2 (M+1)⁺. ¹H NMR (benzene-d₆, 500 MHz, 1:1mixture of atropisomers): δ 7.60 (s, 1.5H), 7.45 (s, 0.5H), 7.31-7.25(m, 3H), 6.98-6.94 (m, 1H), 6.87-6.82 (m, 1H), 6.43-6.37 (m, 1H), 4.54(d, J=15.6 Hz, 0.5H), 4.40-4.36 (m, 1H), 4.47 (d, J=15.6 Hz, 0.5H), 3.96(d, J=15.5 Hz, 0.5H), 3.80 (d, J=15.8 Hz, 0.5H), 3.24-3.15 (m, 1H), 3.02(s, 3H), 2.62-2.58 (m, 0.5H), 2.53-2.48 (m, 0.5H), 2.12-2.07 (m, 0.5H),2.04-2.00 (m, 0.5H) 1.22-1.11 (m, 6 H).

The racemic material was separated by chiral HPLC using 15% IPA/heptaneand an OD column into its two enantiomers.

(5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one:LCMS=624.2 (M+1)⁺. ¹H NMR (benzene-d₆, 500 MHz, 1:1 mixture ofatropisomers): δ 7.62 (s, 1.5H), 7.47 (s, 0.5H), 7.34-7.27 (m, 3H),6.99-6.95 (m, 1H), 6.88-6.83 (m, 1H), 6.44-6.39 (m, 1H), 4.54 (d, J=15.5Hz, 0.5H), 4.47-4.41 (m, 1H), 4.33 (d, J=15.6 Hz, 0.5H), 3.98 (d, J=15.7Hz, 0.5H), 3.82 (d, J=15.8 Hz, 0.5H), 3.24-3.15 (m, 1H), 3.05 (s, 3H),2.67-2.62 (m, 0.5H), 2.57-2.52 (m, 0.5H), 2.16-2.11 (m, 0.5H), 2.09-2.04(m, 0.5H) 1.22-1.11 (m, 6H).

(5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one:LCMS=624.2 (M+1)⁺. ¹H NMR (benzene-d₆, 500 MHz, 1:1 mixture ofatropisomers): δ 7.63 (s, 1.5H), 7.48 (s, 0.5H), 7.35-7.27 (m, 3H),7.00-6.95 (m, 1H), 6.88-6.83 (m, 1H), 6.44-6.38 (m, 1H), 4.54 (d, J=15.8Hz, 0.5H), 4.48-4.42 (m, 1H), 4.34 (d, J=15.8 Hz, 0.5H), 3.99 (d, J=15.8Hz, 0.5H), 3.83 (d, J=15.8 Hz, 0.5H), 3.25-3.15 (m, 1H), 3.05 (s, 3H),2.68-2.63 (m, 0.5H), 2.58-2.53 (m, 0.5H), 2.18-2.12 (m, 0.5H), 2.10-2.05(m, 0.5H) 1.23-1.11 (m, 6H).

Example 73

Step 1:(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To a stirred suspension of sodium hydride (60% dispersion in mineraloil; 1.3 g; 0.0325 mol) in THF (60 mL) at 0° C. under N₂ was addeddropwise a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(Example 17) (4.077 g; 0.013 mol) in THF (50 mL). Gas evolution wasobserved. The resultant mixture stirred at 0° C. for 30 min prior toaddition of a solution of2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (4.754 g; 0.013 mol)in THF (20 mL). The reaction was allowed to warm to room temperature andstirred for 14 h. The reaction was carefully quenched with H₂O (15 mL)and partitioned between EtOAc (250 mL) and H₂O (75 mL). The aqueouslayer was extracted with EtOAc (3×100 mL). Combined organic layers werewashed with brine (100 mL), dried (MgSO₄), filtered and concentrated invacuo. The residue was purified by flash chromatography (0-20%EtOAc/hexanes gradient) to afford 6.4 g (82.5%) of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-oneas a white solid. LCMS=598.1 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 8.03 (d,J=8.2 Hz, 1H), 7.90 (s, 1H), 7.79 (s, 2H), 7.58 (s, 1H), 7.30 (dd, J=8.2Hz, J=2.0 Hz, 1H), 5.76 (d, J=8 Hz, 1H), 4.88 (d, J=15.8 Hz, 1H), 4.37(d, J=15.8 Hz, 1H), 4.09-4.02 (m, 1H), 0.8 (d, J=6.6 Hz, 3H).

Step 2:(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-methyl}-4-methyl-1,3-oxazolidin-2-one

A stirred mixture of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one(4.29 g; 7.19 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid(Example 78) (4.57 g; 21.57 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0 g; 0.86 mmol), and sodium carbonate (6.35 g) in C₆H₆/EtOH/H₂O(120 mL/17 mL/51 mL) was heated at reflux (100° C.) under N₂ for 14 h.The reaction was partitioned between EtOAc (200 mL) and H₂O (100 mL).The aqueous phase was extracted with EtOAc (3×200 mL). The combinedorganic phases were washed with brine (100 mL), dried (MgSO₄), filteredand concentrated in vacuo. The residue was purified by silica-gel flashchromatography (0-25% EtOAc/hexanes gradient) to afford(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-oneas a yellow solid. To remove the yellow impurity, 2.7 g were dissolvedin 165 mL EtOH and 275 mg decolorizing charcoal was added (activatedcarbon, Darco, G-60, 100 mesh powder, Aldrich). The mixture was stirredat room temperature for 40 min, filtered, and concentrated in vacuo.Trituration with ca. 25 mL hexanes afforded 2.46 g of the title compoundas a white solid. ¹H NMR indicated trace impurities which were removedby silica gel flash chromatography (0-15% EtOAc/hexanes gradient).Residual solvent was removed by lyophilization from acetonitrile.LCMS=638.3 (M+1)⁺. ¹H NMR (benzene-d₆, 500 MHz, 1:1 mixture ofatropisomers): δ 7.82 (s, 0.5H), 7.60 (s, 0.5H), 7.57 (s, 1H), 7.33 (d,J=8 Hz, 1H), 7.27 (d, J=9.9 Hz, 2H), 7.02-6.98 (m, 1H), 6.89 (d, J=8.5Hz, 0.5H), 6.82 (d, J=8.5 Hz, 0.5H), 6.45 (d, J=12.1 Hz, 0.5H), 6.35 (d,J=11.9 Hz, 0.5H), 4.94 (d, J=16.0 Hz, 0.5H), 4.87 (d, J=15.8 Hz, 0.5H),4.54 (d, J=8.0 Hz, 0.5H), 4.50 (d, J=7.8 Hz, 0.5H), 3.74-3.66 (m, 1H),3.23-3.15 (m, 1H), 3.12 (s, 1.5H), 2.99 (s, 1.5H), 2.97-2.92 (m, 0.5H),2.89-2.84 (m, 0.5H), 1.21-1.09 (m, 6H), −0.27 (d, J=6.7 Hz, 1.5H), −0.40(d, J=6.7 Hz, 1.5H).

Alternate procedure for making(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

A mixture of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one(50 mg; 0.084 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid(EXAMPLE 78, 22 mg; 0.105 mmol), palladium acetate (6 mg; 0.0103 mmol),and potassium carbonate (29 mg; 0.257 mmol) in 5:1 acetone/water (6 mL)was heated at reflux for 1 h. Acetone was removed in vacuo and theresidue was diluted with H₂O (10 mL) and extracted with CH₂Cl₂ (3×10mL). The combined extracts were washed with brine (10 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified byflash chromatography (0-25% EtOAc/hexanes gradient) to afford(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-oneas a clear glass. This product can also be made by the method providedin Example 372.

Example 74

(4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methylimidazolidin-2-oneStep A:(4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

((4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one)(46.2 mg, 0.148 mmol) was placed in a dry flask and DMA (3 mL) wasadded. NaHMDS (296 μL of a 1M solution in THF, 0.296 mmol) was added andthe reaction was stirred for 5 min. At this time,2′-(bromomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-yl methylether (80.0 mg, 0.207 mmol) was added by cannula in DMA (2 mL). After 30min, the reaction was quenched with saturated NH₄Cl (2 mL). The mixturewas diluted with EtOAc (40 mL). The organic layer was washed with water(15 mL), and brine (15 mL), dried over Na₂SO₄, filtered, andconcentrated. Purification of the residue by flash chromatography with25% EtOAc/hexanes afforded(4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.27 (25% EtOAc/hexanes). LCMS=620.2 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz; atropisomers present) δ 6.90-7.88 (m, 9H), 4.04-5.05 (m, 3H),3.25-3.74 (m, 4H), 2.88 (m, 1H), 1.19-1.24 (m, 6H), 0.99-1.07 (m, 3H).

Step B:(1S,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propan-1-ol

To a solution of(4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one(147.7 mg, 0.239 mmol) in EtOH (7.5 mL) was added H₂O (1.5 mL) and KOH(150 mg, 2.67 mmol). The solution was heated to 75° C. for 30 h and thencooled to room temperature. EtOAc (75 mL) was added and the organiclayer was washed with H₂O (15 mL) and brine (2×15 mL). The organic layerwas dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by flash chromatography to afford(1S,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propan-1-ol.R_(f)=0.44 (40% EtOAc/hexanes). LCMS=594.2 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 6.93-7.78 (m, 9H), 3.51-4.20 (m, 6H), 2.91 (m, 1H), 2.49 (m, 1H),1.22-1.26 (m, 6H), 0.79-0.81 (m, 3H).

Step C:tert-butyl{(1S,2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1-methylethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate

To a solution of(1S,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propan-1-ol(135.5 mg, 0.228 mmol) in CH₂Cl₂ (5 mL) was added BOC₂O (49.7 mg, 0.228mmol). The reaction was stirred at room temperature for 2 days; duringthis time, 2 additional portions of BOC₂O (25 mg each) were added. After2 days, the reaction was concentrated, and the residue was purified byflash chromatography with 20% EtOAc/hexanes to affordtert-butyl{(1S,2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1-methylethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate.R_(f)=0.41 (40% EtOAc/hexanes). LCMS=594.2 (M+1−BOC)⁺.

Step D:tert-butyl{(1S,2R)-2-azido-2-[3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate

A dry flask was charged with THF (1 mL) diethyl azodicarboxylate (DEAD)(11 μL, 0.0698 mmol) and diphenylphosphoryl azide (DPPA) (15 μL, 0.0698mmol).tert-butyl{(1S,2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1-methylethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate(20.7 mg, 0.0698 mmol) was added by cannula in THF (1 mL). Next Ph₃P(18.3 mg, 0.0698 mmol) was added. The reaction was stirred at roomtemperature for 30 min, and then additional DEAD (11 μL, 0.0698 mmol),DPPA (15 μL, 0.0698 mmol), and Ph₃P (18.3 mg, 0.0698 mmol) were added.After an additional 30 min, the reaction was diluted with EtOAc (40 mL)and washed with water and brine (15 mL each). The organic layer wasdried over Na₂SO₄, filtered, and concentrated. Purification of theresidue by flash chromatography with 15% EtOAc/hexanes affordedtert-butyl{(1S,2R)-2-azido-2-[3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate.R_(f)=0.60 (25% EtOAc/hexanes). LCMS=619.3 (M+1−BOC)⁺.

Step E:(1R,2S)-1-azido-1-[3,5-bis(trifluoromethyl)phenyl]-N-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propan-2-amine

To a solution oftert-butyl{(1S,2R)-2-azido-2-[3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate(21.7 mg, 0.030 mmol) in CH₂Cl₂ (2 mL) was added TFA (200 mL). Thereaction was stirred at room temperature for 1 hour and then dilutedwith CH₂Cl₂ (25 mL). The CH₂Cl₂ solution was washed with 1 N NaOH (15mL) and the aqueous phase was re-extracted with CH₂Cl₂ (25 mL). Theorganic extracts were combined, washed with brine (20 mL), dried overNa₂SO₄, filtered, and concentrated. Purification of the residue by flashchromatography with 15% EtOAc/hexanes afforded(1R,2S)-1-azido-1-[3,5-bis(trifluoromethyl)phenyl]-N-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propan-2-amine.R_(f)=0.45 (15% EtOAc/hexanes). LCMS=619.2 (M+1)⁺.

Step F:(1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N²-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-methyl}propane-1,2-diamine

To a solution of(1R,2S)-1-azido-1-[3,5-bis(trifluoromethyl)phenyl]-N-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propan-2-amine(17.8 mg, 0.0288 mmol) in THF (3 mL) was added PtO₂ (12 mg, 0.053 mmol).The reaction was placed under hydrogen balloon atmosphere and stirred atroom temperature for 3 h. The catalyst was removed by filtration and thefiltrate was concentrated. The residue was put through a short plug ofsilica gel with 0-10% MeOH/CH₂Cl₂ to give(1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N²-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propane-1,2-diamine.LCMS=619.2 (M+1)⁺.

Step G:(4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methylimidazolidin-2-one

A solution of(1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N²-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propane-1,2-diamine(8.0 mg, 0.0135 mmol) in CH₂Cl₂ (2 mL) was cooled to 0° C. and DIPEA (14μL, 0.081 mmol) was added followed by triphosgene (2 mg, 0.00657 mmol).The reaction was stirred at 0° C. for 30 min and then diluted with EtOAc(30 mL). The reaction was washed with saturated NaHCO₃ (10 mL) and brine(10 mL). The organic layer was dried over Na₂SO₄, filtered, andconcentrated. Purification of the residue by flash chromatography with40% EtOAc/hexanes afforded(4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methylimidazolidin-2-one.R_(f)=0.24 (40% EtOAc/hexanes). LCMS=619.2 (M+1)⁺. ¹H NMR (CD₂Cl₂, 600MHz; atropisomers present) δ 6.91-7.84 (m, 9H), 3.84-4.94 (m, 4H),3.64-3.80 (m, 4H), 2.88 (m, 1H), 1.18-1.26 (m, 6H), 0.27-0.42 (m, 3H).

Example 75

(3S,4R)-4-[3,5-bis(trifluoromethyl)phenyl]-2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-3-methyl-1,2,5-thiadiazolidine1,1-dioxide

A glass reaction tube was charged with(1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N²-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propane-1,2-diamine(15.9 mg, 0.0269 mmol), sulfamide (4 mg, 0.0403 mmol), and pyridine (600μL). The tube was flushed with N₂, sealed, and heated at 120° C. for 2h. The reaction was then cooled to room temperature, diluted with EtOAc(40 mL) and washed with H₂O, 1N HCl, and brine (10 mL each). The organiclayer was dried over Na₂SO₄, filtered, and concentrated. Purification ofthe residue by flash chromatography with 25% EtOAc/hexanes afforded(3S,4R)-4-[3,5-bis(trifluoromethyl)phenyl]-2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-3-methyl-1,2,5-thiadiazolidine1,1-dioxide. R_(f)=0.27 (25% EtOAc/hexanes). LCMS=655.2 (M+1)⁺. ¹H NMR(C₆D₆, 500 MHz; atropisomers present) δ 6.51-8.19 (m, 9H), 3.64-4.53 (m,4H), 3.00-3.18 (m, 4H), 2.73 (m, 1H), 1.13-1.20 (m, 6H), −0.03-0.09 (m,3H).

Example 76

2-fluoro-1-isopropenyl-4-methoxybenzene Step A:2-(2-fluoro-4-methoxyphenyl)propan-2-ol

To a solution of 2′-fluoro-4′-methoxyacetophenone (4.45 g, 26.5 mmol) inTHF (50 ml) at 0° C., a solution of 2.4 M MeMgBr (11.6 mmol, 27.8 mmol)was added. The mixture was stirred at 0° C. and then room temperaturefor 4 h. The reaction was quenched with saturated ammonium chloridesolution. The organic was extracted with ethyl acetate (3×50 ml). Thecombined ethyl acetate layers were washed with brine and dried oversodium sulfate. The resulting alcohol was obtained as an oil after flashcolumn using EtOAc:hexane=2:8 as the elute.

Step B: 2-fluoro-1-isopropenyl-4-methoxybenzene

To a solution of 2-(2-fluoro-4-methoxyphenyl)propan-2-ol from Step A(3.89 g, 21.14 mmol) in methylene chloride (50 ml) at 0° C., MsCl (1.95ml, 25.4 mmol) and triethylamine (6.52 ml, 46.5 mmol) were added. Thesolution was stirred at 0° C. and then room temperature for 2 h. Thesolution was diluted with methylene chloride (100 ml), washed withwater, and dried over sodium sulfate. The title compound was obtained asan oil after flash column using EtOAc:hexane=1:9 as the elute. ¹H NMR(CDCl₃, 500 MHz) δ 7.25 (t, J=9.0 Hz, 1H), 6.68 (dd, J=8.5, 2.5 Hz, 1H),6.63 (dd, J=13, 2.5 Hz, 1H), 5.20 (d, J=17.0 Hz, 2H), 3.82 (s, 3H), 2.18(s, 3H).

Alternate route to make 2-fluoro-1-isopropenyl-4-methoxybenzene

A solution of sodium bis(trimethylsilyl)-amide, 1.0M in tetrahydrofuran(714 ml, 0.714 m) was added to a suspension ofmethyltriphenylphosphonium bromide (255 g, 0.714 m) in THF (2.50 L)cooled with an ice bath. The resultant yellow colored suspension wasstirred for 30 minutes at ice bath temperature and then cooled to −78°C. A total of 2-fluoro-4-methoxyacetophenone (100 g, 0.595 m) in THF(200 ml) was added dropwise and stirred at −78° C. for 1.5 hours.Reaction mixture was allowed to warm to room temperature for one hour,quenched with acetic acid (˜80 ml) where color change was observed fromyellow to off white and stirred for 30 minutes (pH˜7)(slight exothermnoted). The mixture was concentrated to a slush, diluted with 7:2hexane:ethyl acetate, and was allowed to sit overnight. Solids wereremoved by filtration and the filtrate was concentrated to yellow oil.The title compound was obtained after flash column using 9:1hexane:ethyl as the eluant.

Example 77

1-fluoro-4-iodo-2-isopropyl-5-methoxybenzene

A solution of the 2-fluoro-1-isopropenyl-4-methoxybenzene (Example 76,1.96 g, 11.81 mmol) in MeOH (30 ml) was charged with hydrogen at 1 atmwith catalytic amount of Pd/C. The mixture was stirred at roomtemperature for 1 h. The mixture was filtered through Celite. Thefiltrate was then added to a mixture of silver sulfate (3.68 g, 11.81mmol) and Iodine (3.00 g, 11.81 mmol) in MeOH (10 ml). The mixture wasstirred at room temperature for 3 h until the color of solution becamelight yellow. The mixture was filtered and the filtrate wasconcentrated. The title compound was obtained after flash column usingEtOAc:hexane 5:95 as the elute. ¹H NMR (CDCl₃, 500 MHz) δ 7.61 (d, J=8.0Hz, 1H), 6.56 (d, J=12.5 Hz, 1H), 3.90 (s, 3H), 118 (m, 1H), 1.28 (m,6H).

Example 78

(4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid

To a solution of 1-fluoro-4-iodo-2-isopropyl-5-methoxybenzene (Example77, 2.61 g, 8.88 mmol) in THF at −78° C., n-BuLi (4.26 ml, 10.65 mmol,2.5 M) was added dropwise. The solution was stirred at −78° C. for 30min. Trimethyl borate (2.98 ml, 26.6 mmol) was added. The solution wasthen stirred at −78° C. for 3 h. The reaction was quenched at −78° C.with saturated ammonium chloride and the mixture was warmed to roomtemperature. The organic was extracted with ethyl acetate (3×50 ml). Thecombined ethyl acetate layers were washed with brine and dried oversodium sulfate. The title compound was obtained as a solid pure enoughfor next step. Further purification with silica gel caused decompositionof product. ¹H NMR (CDCl₃, 500 MHz) δ 7.74 (d, J=10.0 Hz, 1H), 6.62 (d,J=12.5 Hz, 1H), 5.65 (br s, 2H), 3.92 (s, 3H), 3.20 (m, 1H), 1.22 (m,6H).

The boronic acid intermediate can also be made by the following 4-stepprocess:

Conversion of 1 to 2:

THF (24 L) was added to a 100 L cylindrical vessel at room temperature.To this was added 2.75 kg of CeCl₃. The resultant slurry was aged atroom temperature for 1.5 hours. A sample was then examined under amicroscope to confirm that the desired form change had occurred. Theslurry was cooled to 9° C. and MeMgCl was added. The rate of additionwas adjusted to maintain internal temperature below 19° C. The mixturewas cooled to −11° C., and a solution of acetophenone 1 (4.0 kg dilutedto 10 L with THF) was added dropwise, maintaining the internaltemperature below 0° C. The reaction mixture was then aged at atemperature below 0° C. for an hour. The reaction was quenched with 5.7L of 3N HCl in a dropwise fashion, maintaining the internal temperaturebelow 15° C. The quenched reaction mixture was then aged at 5-10° C. for1.5 hours and was filtered through a plug of Solka Floc.

Hydrogenation of 2 to 3:

The THF solution of 2 was solvent switched into ethanol (˜18 L volume),and 1.9 L HCl was added, followed by 190 gm of 10% Pd/C (50% water). Themixture was placed under 15 psi hydrogen at 40° C. until the reactionwas complete based on HPLC analysis. The mixture was cooled to roomtemperature. The catalyst was removed by filtration using Solka-Flok asa filter aid. The anisole product in ethanol was then solvent switchedinto acetonitrile for the next step.

Bromination of 3 to 4:

Anisole 3 is diluted in acetonitrile (1.72 L, 4 mL MeCN/mMol 3). Thismixture is warmed to 35° C., and NB S (1.1 eq, 84 g) is added in asingle solid addition. The reaction is complete in 2-4 hours. Thesolution is concentrated to 400 mL total volume and diluted with 1 L oftoluene. The solution is then washed with sodium thiosulfate and waterto remove the succinimide by-product. The organic layer is thenconcentrated and solvent switched to toluene.

Conversion of Aryl Bromide 4 to Boronic Acid 5:

A 75 L glass reaction vessel was charged with 1.87 kg of aryl bromide 4(7.6 Mol), which was added as 6.4 kg of a 29.1 wt % solution of 4 intoluene. This solution was diluted with 5.6 L of THF. The vessel wasflushed with nitrogen, and tri-isopropylborate (1.35 eq, 2.35 L, 10.3Mol) was added. The mixture was cooled to <−70° C. Then 5. 9 L of 1.6 Mn-BuLi in hexanes (9.5 Mol) was added slowly over 4 hours, maintaining atemperature of <−55° C. Thirty minutes after completion of the n-BuLiaddition, the reaction was complete by LC analysis. The reaction waswarmed to −35° C. and quenched into 3.0 M H₂SO₄ solution (5.6 L). Theaqueous phase after the quench should be acidic (pH˜2). MTBE (7.5 L) wasadded to the mixture to dilute the organic layer. The mixture wasstirred (15 min) and the aqueous layer was cut away. The organic layerwas washed with another 5.6 L of a 3.0 M H₂SO₄ solution (15 min). Afterseparating layers again, the organic MTBE/Toluene layer was extractedtwice with 1 M KOH (15.1 L first and then 7.6 L). The two KOHextractions were combined, diluted with 2-propanol (6.4 L), and cooledto 15° C. Then the solution was slowly acidified to pH ˜2 using 3.0 Msulphuric acid (˜7.6 L) while maintaining temperature at 15-20° C. Theresulting slurry was stirred for 1 h and then filtered. The filter cakewas washed with water (2×6 L) and dried under an air flow for 1 day. Thefiltered solid was placed in an oven under vacuum at 50° C. for 2-3 daysto decompose a diaryl impurity and to dry the solid. The off-whitecrystalline solid was isolated to yield 1.59 kg of boronic acid 5.

Example 79

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-chloro-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-oneStep A: 1-bromo-2-(bromomethyl)-4-chlorobenzene

A mixture of 2-bromo-5-chloro-toluene (2.00 g, 9.75 mmol), NBS (2.08 g,11.7 mmol) and catalytic amount of AIBN in carbon tetrachloride (50 ml)was stirred under refluxing conditions for 4 h. TLC (EtOAc:hexane=5:95)showed no starting material. The mixture was filtered and the filtratewas concentrated. The title compound was obtained as a white solid afterflash column using EtOAc:hexane=5:95 as the elute. ¹H NMR (CDCl₃, 500MHz) δ 7.53 (d, J=9.0 Hz, 1H), 7.47 (d, J=2.5 Hz, 1H), 7.18 (dd, J=8.5,2.5 Hz, 1H), 4.60 (s, 2H).

Step B.(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-chlorobenzyl)-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(0.050 g, 0.16 mmol) in THF (1 ml) at 0° C., NaH (7.6 mg, 0.19 mmol,60%) was added. The mixture was stirred at 0° C. for 30 min. The titlecompound from Step A (0.059 g, 0.21 mmol) was added. The whole mixturewas stirred at 0° C. for 1 h and warmed to room temperature for 4 h. Thereaction was quenched with saturated ammonium chloride. The organic wasextracted with ethyl acetate (3×15 ml). The combined ethyl acetatelayers were washed with brine and dried over sodium sulfate. The titlecompound was obtained after preparative TLC purification usingEtOAc:hexane=2:8 as the elute. ¹H NMR (CDCl₃, 500 MHz) δ 7.92 (s, 1H),7.82 (s, 2H), 7.55 (d, J=8.5 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H), 7.23 (dd,J=8.5, 2.5 Hz, 1H), 5.77 (d, J=8.0 Hz, 1H), 4.86 (d, J=16.0 Hz, 1H),4.36 (d, J=16.0 Hz, 1H), 4.11 (m, 1H), 0.82 (d, J=6.5 Hz, 3H).

Step C.(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-chloro-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

A mixture of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-chlorobenzyl)-4-methyl-1,3-oxazolidin-2-one(44 mg, 0.085 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid(Example 78, 23 mg, 0.11 mmol), potassium carbonate (25 mg, 0.18 mmol)and catalytic amount of PdOAc in a 4:1 mixture of acetone/water washeated to reflux for 1 h. Acetone was removed and water was added. Theorganic was extracted with methylene chloride (3×15 ml). The combinedmethylene chloride layers were washed with brine and dried over sodiumsulfate. The title compound was obtained as a solid after preparativereverse phase HPLC. ¹H NMR (CDCl₃, 500 MHz) δ 1:1 mixture of rotamer δ7.90 (s, 1H), 7.73 (s, 2H), 7.49 (m, 1H), 7.40 (m, 1H), 7.20 (m, 1H),7.00 (m, 1H), 6.68 (dd, J=12.0, 3.0 Hz, 1H), 5.63 (d, J=8.0 Hz, ½H),5.44 (d, J=8.0 Hz, ½H), 4.85 (d, J=10.0 Hz, ½H), 4.82 (d, J=10.0 Hz,½H), 4.03 (d, J=16.0 Hz, ½H), 3.84 (m, 1½H), 3.80 (s, 3H), 3.20 (m, 1H),1.20 (m, 6H), 0.56 (d, J=6.5 Hz, 3/2H), 0.38 (d, J=6.5H, 3/2H). LC-MS(M+1): 604.3, 4.61 min.

Example 80

5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one Step A:2-iodo-5-(trifluoromethyl)benzaldehyde

To a solution of 2-iodo-5-(trifluoromethyl)benzonitrile (EXAMPLE 2, 42g) in CH₂Cl₂ (300 mL) at −78° C. was added a solution of DIBAL in CH₂Cl₂(175 mL, 1M) over 30 minutes. A precipitate formed. The reaction waswarmed to 0° C. An additional 25 mL of the DIBAL solution was addeddropwise over 30 minutes. The reaction was poured into 200 mL 2N aqueousHCl, diluted with ether and stirred 1 hour. TLC analysis indicates iminestill present and an additional 100 mL 2N aqueous was added and thereaction stirred overnight. Imine was still present by TLC analysis and200 mL 2N aqueous HCl was added and the mixture stirred 2 hours. Thelayers were separated and the aqueous layer back extracted with ether.The ether extracts were combined, washed with brine, dried overanhydrous MgSO₄, filtered and concentrated. The product was purified bysilica gel chromatography eluting with 95:5 hexanes/EtOAc to give2-Iodo-5-(trifluoromethyl)benzaldehyde as a white solid. ¹H NMR (500MHz, CDCl₃): δ 10.00 (s, 1H), 8.12 (s, 1H), 8.11 (d, J=8 Hz, 1H), 7.53(dd, J=2 Hz, 8 Hz, 1H).

Step B: 5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one

To a 0° C. solution of 0.2 g of 2-iodo-5-(trifluoromethyl)benzaldehydein 3 mL of EtOH was added 0.13 mL of nitromethane, then 0.28 mL of a 2.5N solution of NaOH. The mixture was stirred at 0° C. for 3 h, and thenneutralized by addition of 2.1 mL of a 0.33 N aqueous solution of AcOH.The mixture was partitioned between 10 mL of water and 10 mL of EtOAc.The aqueous phase was extracted with 2×5 mL of EtOAc. The combinedorganics were washed with 10 mL of brine, dried over Na₂SO₄, andconcentrated. The residue was dissolved in 4 mL of MeOH and 0.5 mL of88% aqueous formic acid was added. Approximately 200 mg of a Raneynickel slurry was added and the mixture was flushed with H2, and stirredunder an H2 balloon for 4 h. The mixture was filtered through a pad ofCelite, washing with MeOH, and the filtrate was concentrated. Theresidue was partitioned between 10 mL of 10% aqueous NH₄OH and 20 mL ofEtOAc. The aqueous phase was extracted with 2×10 mL of EtOAc. Thecombined organics were washed with 10 mL of brine, dried over Na₂SO₄,and concentrated. The residue was dissolved in 2 mL of CH₂Cl₂. To thesolution was added 0.114 mL of diisopropylethylamine, then 0.065 g oftriphosgene. The mixture was stirred at 0° C. for 30 min, then dilutedwith 10 mL of EtOAc and 10 mL of saturated NaHCO₃. The aqueous phase wasextracted with 2×10 mL, of EtOAc. The combined organics were washed with10 mL of brine, dried over Na₂SO₄, and concentrated. The residue waspurified by flash chromatography on a Biotage Horizon, 25S column,eluting with 1 CV of 4% EtOAc in hexanes, followed by a linear gradientof EtOAc in hexanes from 4 to 100% over 10 CV to provide the titlecompound. Mass spectrum (ESI) 350.0 (M+1). ¹H NMR (500 MHz, CDCl₃): δ8.00 (d, J=8 Hz, 1H), 7.74 (br s, 1H), 7.33 (br d, J=8 Hz, 1H), 5.80(dd, J=7 Hz, 9 Hz 1H), 5.05-5.50 (br, 1H), 4.28 (t, J=9 Hz, 1.5H), 3.36(dd, J=7 Hz, 9 Hz, 1H).

Example 81

5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one

To a solution of 65 mg of5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one,45 mg of (5-isopropyl-2-methoxyphenyl)boronic acid, and 66 mg ofpotassium carbonate in 6 mL of acetone and 1.5 mL of water was added ca.5 mg of palladium acetate. The mixture was heated to reflux and stirredat this temperature for 1.5 h. Acetone was removed by rotary evaporationand the residue was diluted with 10 mL of EtOAc and 10 mL of water. Theaqueous phase was extracted with 10 mL of EtOAc. The combined organicswere washed with 10 mL of brine, dried over Na₂SO₄, and concentrated.The residue was purified by flash chromatography on a Biotage Horizon,25S column, eluting with 1 CV of 10% EtOAc in hexanes, followed by alinear gradient of EtOAc in hexanes from 10 to 100% over 10 CV toprovide the title compound. Spectral data are provided in EXAMPLE 49.

Following the procedures outlined in EXAMPLE 52 the compounds listed inTable 2 were prepared:

TABLE 3

LC/MS Data EXAMPLE R (M + 1) 82

488.1 83

504.1 84

495.1 85

476.2 86

484.2 87

484.2 88

484.2 89

484.2

Example 90

5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

Following the procedure described in EXAMPLE 80 and using nitroethane,0.2 g of 2-iodo-5-(trifluoromethyl)benzaldehyde provided 0.102 g of thedesired product, which was separated into the cis and transdiastereomers by flash chromatography Biotage Horizon, 25S column,eluting with 1 CV of 10% EtOAc in hexanes, followed by a linear gradientof EtOAc in hexanes from 10 to 100% over 10 CV.

trans-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one:Mass spectrum (ESI) 372.1 (M+1). ¹H NMR (500 MHz, CDCl₃): δ 8.02 (d, J=8Hz, 1H), 7.61 (d, J=1.5 Hz, 1H), 7.32 (dd, J=2 Hz, 8 Hz, 1H), 6.16 (s,1H), 5.39 (d, J=4 Hz, 1H), 3.76 (dq, J=6 Hz, 4.5 Hz, 1H), 1.62 (d, J=6Hz, 3H).

cis-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one:Mass spectrum (ESI) 372.1 (M+1). ¹H NMR (500 MHz, CDCl₃): δ 7.98 (d, J=8Hz, 1H), 7.60 (br s, 1H), 7.33 (dd, J=1.5 Hz, 8 Hz, 1H), 6.25 (s, 1H),5.85 (d, J=8 Hz, 1H), 3.76 (dq, J=8 Hz, 7 Hz, 1H), 0.81 (d, J=7 Hz, 3H).

Example 91

trans-5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one(racemic)

To a solution of 0.036 g oftrans-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one,0.024 g of (5-isopropyl-2-methoxyphenyl)boronic acid, and 0.04 g ofpotassium carbonate in 2 mL of acetone and 0.5 mL of water was added ca.2 mg of palladium acetate. The mixture was heated to reflux and stirredat this temperature for 1.5 h. Acetone was removed by rotary evaporationand the residue was diluted with 10 mL of EtOAc and 10 mL of water. Theaqueous phase was extracted with 10 mL of EtOAc. The combined organicswere washed with 10 mL of brine, dried over Na₂SO₄, and concentrated.The residue was purified by flash chromatography on a Biotage Horizon,25S column, eluting with 1 CV of 10% EtOAc in hexanes, followed by alinear gradient of EtOAc in hexanes from 10 to 100% over 10 CV toprovide the title compound. Mass spectrum (ESI) 394.2 (M+1). ¹H NMRsignals are doubled because of atropoisomerism. ¹H NMR (500 MHz, CDCl₃):δ 7.80, 7.78 (s, 1H), 7.64, 7.63 (d, J=8 Hz, 1H), 7.35 (d, J=7.5 Hz,1H), 7.27, 7.26 (d, J=8 Hz 1H), 7.00, 6.95 (d, J=2.5 Hz, 1H), 6.93, 6.92(d, J=8 Hz, 1H), 5.87, 5.81 (s, 1H), 5.16, 5.10 (d, J=5 Hz, 1H),3.70-3.78 (m, 3.5H), 3.49 (m, 0.5H), 2.89 (m, 1H), 1.24 (m, 6H), 0.90,0.70 (d, J=6.5 Hz, 3H).

Example 92

cis-5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one(racemic)

Following the procedure described in EXAMPLE 91, 0.046 g ofcis-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-oneprovided the desired product. Mass spectrum (ESI) 394.2 (M+1). ¹H NMRsignals are doubled because of atropoisomerism. ¹H NMR (500 MHz, CDCl₃):δ 7.89, 7.88 (s, 1H), 7.65, 7.64 (d, J=7.5 Hz, 1H), 7.34, 7.32 (d, J=8Hz, 1H), 7.26 (d, J=8.5 Hz, 1H), 6.98, 6.86 (d, J=2.5 Hz, 1H), 6.91,6.89 (d, J=8 Hz, 1H), 5.83, 5.75 (s, 1H), 5.69, 5.61 (d, J=8 Hz, 1H),3.75 (s, 1.8H), 3.58-3.70 (m, 2H), 3.32 (m, 0.6H), 2.88 (m, 1H), 1.23(m, 6H), 0.89, 0.71 (d, J=6.5 Hz, 3H).

Example 93

trans-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one(racemic)

To a 0° C. solution of 30 mg oftrans-5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-onein 1 mL of DMF was added 8 mg of sodium hydride. The mixture was stirred10 min at room temperature, and then 32 mg of3,5-bis(trifluoromethyl)benzyl bromide was added. The mixture wasstirred overnight at room temperature, then diluted with 10 mL of EtOAcand 10 mL of water. The phases were separated and the aqueous phase wasextracted with 5 mL of EtOAC. The combined organics were washed with 5mL of brine, dried (Na₂SO₄), and concentrated. The residue was purifiedby flash chromatography on a Biotage Horizon, 25S column, eluting with 1CV of 4% EtOAc in hexanes, followed by a linear gradient of EtOAc inhexanes from 4 to 100% over 10 CV to provide the title compound. Massspectrum (ESI) 620.2 (M+1). ¹H NMR signals are doubled because ofatropoisomerism. ¹H NMR (500 MHz, CDCl₃): δ 7.53-7.80 (m, 5H), 7.33 (d,J=8 Hz, 1H), 7.21-7.29 (m, 1H), 7.00, 6.76 (d, J=2.5 Hz, 1H), 6.91, 6.86(d, J=8.5 Hz, 0.4H), 5.15, 5.10 (d, J=4.5 Hz, 1H), 4.80, 4.74 (d, J=16Hz, 1H), 4.25, 4.21 (d, 16 Hz, 1H), 3.76 (s, 2H), 3.49 (s, 1H), 3.43 (m,0.4H), 3.18 (m, 0.5H), 2.77-2.98 (m, 1H), 1.24 (m, 3H), 1.16 (m, 3H),0.78, 0.61 (d, J=6.5 Hz, 3H).

Example 94

cis-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one(racemic)

Following the procedure described in EXAMPLE 93, 40 mg ofcis-5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-oneand 42 mg of 3,5-bis(trifluoromethyl)benzyl bromide gave the titlecompound. Mass spectrum (ESI) 620.2 (M+1). ¹H NMR signals are doubledbecause of atropoisomerism. ¹H NMR (500 MHz, CDCl₃): δ 7.82-7.94 (m,2H), 7.62-7.74 (m, 3H), 7.39, 7.37 (d, J=8 Hz, 1H), 7.25, 7.17 (br d,J=8.5 Hz, 1H), 7.00, 6.78 (s, 1H), 6.87, 6.84 (d, J=8.5 Hz, 1H), 5.59,5.56 (d, J=4.5 Hz, 1H), 4.96 (d, J=16 Hz, 1H), 4.22, 4.11 (d, J=16 Hz,1H), 3.76 (s, 2H), 3.58 (s, 1H), 3.40 (m, 0.4H), 2.85-3.00 (m, 1H), 2.78(m, 0.5H), 1.23 (d, J=7 Hz, 3H), 1.06 (m, 3H), 0.88, 0.69 (d, J=6.5 Hz,3H).

Example 95

(4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-oneStep A:(4S)-4-benzyl-3-{(2R,3S)-3-hydroxy-3-[2-iodo-5-(trifluoromethyl)phenyl]-2-methylpropanoyl}-1,3-oxazolidin-2-one

A mixture of 1.8 g of5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde(EXAMPLE 80, Step A), 1.16 g of(4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one, 0.048 g of magnesiumchloride, 1.40 mL of triethylamine, and 0.91 mL of chlorotrimethylsilanein 10 mL of EtOAc was stirred at r.t. for 24 h, then filtered through a10×10 cm plug of silica gel, eluting with 400 mL of Et₂O. The filtratewas concentrated, and 10 mL of MeOH was added along with 2 drops oftrifluoroacetic acid. This solution was stirred at r.t. for 30 min andconcentrated to a pale yellow oil. The residue was purified by flashchromatography on a Biotage Horizon, 65 i column, eluting with 15 CV of10% acetone in hexanes to provide the title compound. Mass spectrum(ESI) 516.2 (M−OH). ¹H NMR (500 MHz, CDCl₃): δ 8.00 (d, J=8.5 Hz, 1H),7.76 (d, J=2 Hz, 1H), 7.22-7.32 (m, 4H), 7.07 (br d, J=6.5 Hz, 2H), 5.18(dd, J=6.5 Hz, 7.5 Hz, 1H), 4.67 (m, 1H), 4.46 (dq, J=6.5 Hz, 7.5 Hz,1H), 4.17 (t, J=9 Hz, 1H), 4.11 (dd, J=3 Hz, 9 Hz, 1H), 3.97 (d, J=8 Hz,1H), 3.19 (dd, J=7 Hz, 13.5 Hz, 1H), 2.57 (dd, J=9.5 Hz, 13.5 Hz, 1H),1.34 (d, J=7.5 Hz, 3H).

Step B:(4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

To a 0° C. solution of 0.65 g of(4S)-4-benzyl-3-{(2R,3S)-3-hydroxy-3-[2-iodo-5-(trifluoromethyl)phenyl]-2-methylpropanoyl}-1,3-oxazolidin-2-onein 6 mL of 3:1 tetrahydrofuran-water was added 0.102 g of lithiumhydroxide in 1.5 mL of water, then 0.554 mL of a 30% aqueous solution ofhydrogen peroxide. The solution was stirred 1 h at 0° C., at which pointLC/MS analysis showed no starting material. A 1.5 M solution of sodiumsulfite (3.7 mL) was added to the cold solution, which was then pouredinto a separatory funnel and extracted with 2×10 mL of CH₂Cl₂. Thecombined CH₂Cl₂ extracts were back-extracted with 20 mL of 3:1water-saturated aqueous NaHCO₃. The combined aqueous layers wereacidified (pH<1) with 6 N HCl and extracted with 4×10 mL of EtOAc. Thecombined EtOAc extracts were washed with 10 mL of brine, dried overNa₂SO₄, and concentrated. The residue was dissolved in 10 mL of toluene.Diphenylphosphoryl azide (0.315 mL) and 0.24 mL of triethylamine wereadded and the mixture was stirred overnight at 100° C., then cooled andconcentrated. The residue was purified by flash chromatography on aBiotage Horizon, 40S column, eluting with 1 CV of 5% EtOAc in hexanes,followed by a linear gradient of EtOAc in hexanes from 5 to 100% over 10CV to provide the title compound. Mass spectrum (ESI) 372.1 (M+1). ¹HNMR (500 MHz, CDCl₃): δ 8.02 (d, J=8 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H),7.32 (dd, J=2 Hz, 8 Hz, 1H), 6.16 (s, 1H), 5.39 (d, J=4 Hz, 1H), 3.76(dq, J=6 Hz, 4.5 Hz, 1H), 1.62 (d, J=6 Hz, 3H). Analytical HPLC onChiralpak AD 4.6×250 mm, eluting with 4% ethanol in heptane at 0.75mL/min (t_(R)=21.56 min for R,R; t_(R)=18.00 min for S,S) showed 98%e.e.

Example 96

(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

To a 0° C. solution of 95 mg of(4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-onein 1 mL of DMF was added 20 mg of sodium hydride. The mixture wasstirred 10 min at 0° C.; then 94 mg of 3,5-bis(trifluoromethyl)benzylbromide was added. The mixture was stirred 10 min at 0° C., then dilutedwith 10 mL of EtOAc and 10 mL of water. The phases were separated andthe aqueous phase was extracted with 10 mL of EtOAc. The combinedorganic phases were washed with 10 mL of brine, dried over Na₂SO₄, andconcentrated. The residue was purified by flash chromatography on aBiotage Horizon, 25M column, eluting with 1 CV of 2% EtOAc in hexanes,followed by a linear gradient of EtOAc in hexanes from 2 to 100% over 10CV to provide the title compound. Mass spectrum (ESI) 598.1 (M+1). ¹HNMR (500 MHz, CDCl₃): δ 8.00 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.58 (brs, 3H), 7.34 (dd, J=1.5 Hz, 8 Hz, 1H), 5.36 (d, J=4 Hz, 1H), 4.89 (d,J=16 Hz, 1H), 4.31 (d, J=16 Hz, 1H), 4.48 (dq, J=6 Hz, 4 Hz, 1H), 1.55(d, J=6.5 Hz, 3H).

Example 97

(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one

Following the procedure described in EXAMPLE 81, 41 mg of(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-oneand 17 mg of (5-isopropyl-2-methoxyphenyl)boronic acid gave titlecompound. Mass spectrum (ESI) 620.4 (M+1). ¹H NMR signals are doubledbecause of atropoisomerism. ¹H NMR (500 MHz, CDCl₃): δ 7.53-7.80 (m,5H), 7.33 (d, J=8 Hz, 1H), 7.21-7.29 (m, 1H), 7.00, 6.76 (d, J=2.5 Hz,1H), 6.91, 6.86 (d, J=8.5 Hz, 0.4H), 5.15, 5.10 (d, J=4.5 Hz, 1H), 4.80,4.74 (d, J=16 Hz, 1H), 4.25, 4.21 (d, 16 Hz, 1H), 3.76 (s, 2H), 3.49 (s,1H), 3.43 (m, 0.4H), 3.18 (m, 0.5H), 2.77-2.98 (m, 1H), 1.24 (m, 3H),1.16 (m, 3H), 0.78, 0.61 (d, J=6.5 Hz, 3 Hz).

Example 98

(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one

Following the procedure described in EXAMPLE 81, 38.5 mg of(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-oneand 18 mg of (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (EXAMPLE78) gave the title compound. Mass spectrum (ESI) 638.3 (M+1). ¹H NMRsignals are doubled because of atropoisomerism. ¹H NMR (500 MHz, CDCl₃):δ 7.55-7.80 (m, 5H), 7.29 (d, J=8 Hz, 1H), 7.00, 6.77 (d, J=8.5 Hz, 1H),6.68, 6.63 (d, J=12 Hz, 1H), 5.08, 5.04 (d, J=5 Hz, 1H), 4.81, 4.75 (d,J=16 Hz, 1H), 4.26, 4.23 (d, 15.5 Hz, 1H), 3.75 (s, 2H), 3.50 (s, 1H),3.43 (m, 0.5H), 3.12-3.24 (m, 1.5H), 1.24, 1.22 (d, J=5 Hz, 3H), 1.17,1.06 (d, J=7 Hz, 3H), 0.84, 0.70 (d, J=6 Hz, 3H).

Example 99

(4S,5S)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-oneStep A:(4R)-4-benzyl-3-{(2S,3R)-3-hydroxy-3-[2-iodo-5-(trifluoromethyl)phenyl]-2-methylpropanoyl}-1,3-oxazolidin-2-one

Following the procedure described in EXAMPLE 95, Step A, 0.72 g of5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde(EXAMPLE 80, Step A), 0.466 g of(4R)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one, 0.02 g of magnesiumchloride, 0.56 mL of triethylamine, and 0.38 mL of chlorotrimethylsilaneprovided the title compound. Mass spectrum (ESI) 516.2 (M−OH). ¹H NMR(500 MHz, CDCl₃): δ 8.00 (d, J=8.5 Hz, 1H), 7.76 (d, J=2 Hz, 1H),7.22-7.32 (m, 4H), 7.07 (br d, J=6.5 Hz, 2H), 5.18 (dd, J=6.5 Hz, 7.5Hz, 1H), 4.67 (m, 1H), 4.46 (dq, J=6.5 Hz, 7.5 Hz, 1H), 4.17 (t, J=9 Hz,1H), 4.11 (dd, J=3 Hz, 9 Hz, 1H), 3.97 (d, J=8 Hz, 1H), 3.19 (dd, J=7Hz, 13.5 Hz, 1H), 2.57 (dd, J=9.5 Hz, 13.5 Hz, 1H), 1.34 (d, J=7.5 Hz,3H).

Step B:(4S,5S)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

Following the procedure described in EXAMPLE 95, Step B, 0.214 g of(4R)-4-benzyl-3-{(2S,3R)-3-hydroxy-3-[2-iodo-5-(trifluoromethyl)phenyl]-2-methylpropanoyl}-1,3-oxazolidin-2-one,0.034 g of lithium hydroxide, 0.16 mL of a 30% aqueous solution ofhydrogen peroxide, 0.1 mL of diphenylphosphoryl azide, and 0.072 mL oftriethylamine provide the title compound. Mass spectrum (ESI) 372.1(M+1). ¹H NMR (500 MHz, CDCl₃): δ 8.02 (d, J=8 Hz, 1H), 7.61 (d, J=1.5Hz, 1H), 7.32 (dd, J=2 Hz, 8 Hz, 1H), 6.16 (s, 1H), 5.39 (d, J=4 Hz,1H), 3.76 (dq, J=6 Hz, 4.5 Hz, 1H), 1.62 (d, J=6 Hz, 3H). AnalyticalHPLC on Chiralpak AD 4.6×250 mm, eluting with 4% ethanol in heptane at0.75 mL/min (t_(R)=21.56 min for R,R; t_(R)=18.00 min for S,S) showed99% e.e.

Example 100

(4S,5S)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

Following the procedure described in EXAMPLE 96, 0.108 g of(4S,5S)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one,23 mg of sodium hydride, and 107 mg of 3,5-bis(trifluoromethyl)benzylbromide provided the title compound. Mass spectrum (ESI) 598.1 (M+1). ¹HNMR (500 MHz, CDCl₃): δ 8.00 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.58 (brs, 3H), 7.34 (dd, J=1.5 Hz, 8 Hz, 1H), 5.36 (d, J=4 Hz, 1H), 4.89 (d,J=16 Hz, 1H), 4.31 (d, J=16 Hz, 1H), 4.48 (dq, J=6 Hz, 4 Hz, 1H), 1.55(d, J=6.5 Hz, 3H).

Example 101

(4S,5S)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one

Following the procedure described in EXAMPLE 81, 40 mg of(4S,5S)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-oneand 17 mg of (5-isopropyl-2-methoxyphenyl)boronic acid gave the titlecompound. Mass spectrum (ESI) 620.4 (M+1). ¹H NMR signals are doubledbecause of atropoisomerism. ¹H NMR (500 MHz, CDCl₃): δ 7.53-7.80 (m,5H), 7.33 (d, J=8 Hz, 1H), 7.21-7.29 (m, 1H), 7.00, 6.76 (d, J=2.5 Hz,1H), 6.91, 6.86 (d, J=8.5 Hz, 0.4H), 5.15, 5.10 (d, J=4.5 Hz, 1H), 4.80,4.74 (d, J=16 Hz, 1H), 4.25, 4.21 (d, 16 Hz, 1H), 3.76 (s, 2H), 3.49 (s,1H), 3.43 (m, 0.4H), 3.18 (m, 0.5H), 2.77-2.98 (m, 1H), 1.24 (m, 3H),1.16 (m, 3H), 0.78, 0.61 (d, J=6.5 Hz, 3 Hz).

Example 102

(4R,5R)-5-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one

Following the procedure described in EXAMPLE 81, 240 mg of(4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-oneand 171 mg of (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid(EXAMPLE 78) gave the title compound. Mass spectrum (ESI) 412.3 (M+1).¹H NMR signals are doubled because of atropoisomerism. ¹H NMR (500 MHz,CDCl₃): δ 7.79, 7.77 (s, 1H), 7.64, 7.62 (dd, J=2.5 Hz, 8 Hz, 1H), 7.32,7.31 (d, J=8 Hz, 1H), 7.00, 6.95 (d, J=8.5 Hz, 1H), 6.70, 6.67 (d, J=12Hz, 1H), 6.47, 6.43 (s, 1H), 5.08, 5.04 (d, J=5 Hz, 0.1H), 3.68-3.80 (m,3.5H), 3.53 (m, 0.5H), 3.21 (m, 1H), 1.19-1.30 (m, 6H), 0.95, 0.77 (d,J=6 Hz, 3H).

Following the procedures outlined in EXAMPLE 96 the compounds listed inTable 4 were prepared from(4R,5R)-5-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one:

TABLE 4

LC/MS Data EXAMPLE R (M + 1) 103

520.3 104

520.3 105

520.3 106

538.4 107

516.4 108

516.4 109

503.3 110

571.4

Example 111

((4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methylimidazolidin-2-ylidene)cyanamide

To a solution of(1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N²-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propane-1,2-diamine(25.1 mg, 0.0424 mmol) in dichloroethane (1.5 mL) was addedtriethylamine (15 μL, 0.105 mmol) and diphenyl cyanocarbonimidate (13mg, 0.053 mmol). The reaction was heated at 60° C. overnight, cooled toroom temperature, filtered, and loaded directly onto a silica gel columnfor purification by flash chromatography with 10 to 40% EtOAc/hexanes toafford((4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methylimidazolidin-2-ylidene)cyanamide.R_(f)=0.20 (25% EtOAc/hexanes). LCMS=643.3 (M+1)⁺. ¹H NMR (C₆D₆, 500MHz; atropisomers present, doubling of some peaks) δ 6.53-8.83 (m, 10H),3.61-4.91 (m, 3H), 3.28-2.70 (m, 5H), 1.14-1.25 (m, 6H), −0.39-0.26 (m,3H).

Following the general procedures outlined above, the compounds in Table5 were prepared:

TABLE 5

Compound A³ A² Z LCMS (M + 1) 112

CO 515.1 113

CO 537.3 114

CO 615.3 115

CO 569.3 116

CO 637.3 117

SO₂ 673.3

(4S,5R)-5-(3,5-difluorophenyl)-4-methyl-1,3-oxazolidin-2-one Step A:benzyl [(1S)-2-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate

To a −15° C. solution of benzyl{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (1.96 g,7.36 mmol) in THF (9.4 mL) was added i-propyl magnesium chloride (3.6 mLof a 2M solution in Et₂O, 7.2 mmol). The reaction was stirred at −15° C.for 15 minutes and then 3,5-difluorophenylmagnesium bromide (29.44 mL ofa 0.5 M solution in THF, 14.72 mmol) was added. The reaction was warmedto room temperature and stirred for 24 hours. The reaction was thenpoured into saturated NH₄Cl (100 mL) and extracted with EtOAc (3×100mL). The organic extracts were washed with water and brine (100 mLeach), dried over Na₂SO₄, filtered, and concentrated. Purification ofthe residue by flash chromatography on silica gel (15% EtOAc/hexanes)afforded benzyl[(1S)-2-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate. R_(f)=0.34(15% EtOAc/hexanes). LCMS=342.3 (M+Na)⁺.

Step B: benzyl[(1S,2S)-2-(3,5-difluorophenyl)-2-hydroxy-1-methylethyl]carbamate

To a −78° C. solution of benzyl[(1S)-2-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate. (1.35 g,4.23 mmol) in THF (75 mL) was added L-Selectride (6.35 mL of a 1Msolution in THF, 6.35 mmol). After stirring at −78° C. for 1 hour, thereaction was poured into 1N HCl (50 mL). The mixture was extracted withEtOAc (2×100 mL). The organic extracts were washed with water and brine(50 mL each), dried over Na₂SO₄, filtered, and concentrated.Purification of the residue by flash chromatography on silica gel (5 to40% EtOAc/hexanes) afforded benzyl[(1S,2S)-2-(3,5-difluorophenyl)-2-hydroxy-1-methylethyl]carbamate (majorproduct). LCMS=322.3 (M+1)⁺.

Step C: (4S,5R)-5-(3,5-difluorophenyl)-4-methyl-1,3-oxazolidin-2-one

To a solution of[(1S,2S)-2-(3,5-difluorophenyl)-2-hydroxy-1-methylethyl]carbamate (900mg, 2.80 mmol) in THF (28.6 mL) was added MeOH (14.3 mL) and 7.5 N KOH(7.2 mL). The reaction was stirred at room temperature for 4 hours andthen extracted with EtOAc (2×75 mL). The organic extracts were washedwith water and brine (50 mL each), dried over Na₂SO₄, filtered, andconcentrated. Purification of the residue by flash chromatography onsilica gel (10 to 75% EtOAc/hexanes) afforded(4S,5S)-5-(3,5-difluorophenyl)-4-methyl-1,3-oxazolidin-2-one. R_(f)=0.07(25% EtOAc/hexanes). LCMS=214.3 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ6.89-6.93 (m, 2H), 6.82 (m, 1H), 6.24 (bs, 1H), 5.01 (d, J=6.8 Hz, 1H),3.79 (m, 1H), 1.42 (d, J=6.2 Hz, 3H).

6-chloro-5-fluoro-2-iodopyridin-3-ol

To a solution of 6-chloro-5-fluoropyridin-3-ol (307.8 mg, 2.08 mmol) inwater (11 mL) was added Na₂CO₃ (441 mg, 4.16 mmol) and I₂ (549 mg, 2.08mmol). After 2 hours, the reaction mixture was acidified with 1 N HCl topH 3, diluted with EtOAc (100 mL), and washed with aq. NaHSO₃ and brine(50 mL each). The organic layer was dried over Na₂SO₄, filtered andconcentrated to afford 6-chloro-5-fluoro-2-iodopyridin-3-ol. LCMS=273.9(M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.11 (d, J=8.5 Hz, 1H), 5.47 (d, J=1.4Hz, 1H).

2-bromo-6-isopropenyl-3-methoxypyridine

In a tube were placed 2-bromo-6-iodo-3-methoxypyridine (700 mg, 2.236mmol), isopropenylboronic acid (212 mg, 2.460 mmol), DME (7.5 mL), EtOH(2.8 mL), and 1M aq. Na₂CO₃ (5.6 mL). The mixture was degassed with N₂.Next, Pd(PPh₃)₄ (206 mg, 0.179 mmol) was added and the mixture wasdegassed again with N₂. The tube was sealed and heated at 80° C. for 16hours. The reaction was then cooled to room temperature, diluted withEtOAc (100 mL), and washed with saturated NaHCO₃ and brine (50 mL each).The organic layer was dried over Na₂SO₄, filtered, and concentrated.Purification of the residue by flash chromatography on silica gel (0 to15% EtOAc/hexanes) afforded 2-bromo-6-isopropenyl-3-methoxypyridine.R_(f)=0.38 (25% EtOAc/hexanes). LCMS=230.0 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.36 (d, J=8.5 Hz, 1H), 7.07 (d, J=9.4 Hz, 1H), 5.81 (s, 1H),5.21 (s, 1H), 3.92 (s, 3H), 2.16 (s, 3H).

2-iodo-3-methoxypyridine

To a solution of 2-iodopyridin-3-ol (45.3 mg, 0.205 mmol) in DMF (3 mL)was added Cs₂CO₃ (334 mg, 1.030 mmol) and MeI (25 μL, 0.410 mmol). After1 hour, the reaction was poured into water (10 mL), diluted with EtOAc(20 mL), washed with water (3×10 mL) and brine (10 mL). The organiclayer was dried over Na₂SO₄, filtered, and concentrated to afford2-iodo-3-methoxypyridine. LCMS=236.1 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ8.00 (dd, J=1.4, 4.6 Hz, 1H), 7.20 (dd, J=4.6, 8.0 Hz, 1H), 7.00 (dd,1.4, 8.3 Hz, 1H), 3.90 (s, 3H).

2-bromo-6-iodopyridin-3-ol

To a solution of 2-bromopyridin-3-ol (1.00 g, 5.80 mmol) in water (30mL) was added Na₂CO₃ (1.23 g, 11.60 mmol) and I₂ (1.53 g, 5.80 mmol).After 1 hour, the reaction was quenched with 1 N HCl (20 mL), extractedwith EtOAc (2×100 mL), and washed with aq. NaHSO₃ and brine (50 mLeach). The organic layer was dried over Na₂SO₄, filtered andconcentrated. Purification of the residue by flash chromatography onsilica gel (20 to 40% EtOAc/hexanes) afforded2-bromo-6-iodopyridin-3-ol. R_(f)=0.44 (25% EtOAc/hexanes). LCMS=301.9(M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.56 (d, J=8.3 Hz, 1H), 6.99 (d, J=8.3Hz, 1H), 5.65 (s, 1H).

1-(2-bromo-1,3-thiazol-5-yl)ethanol

To a 0° C. solution of 2-bromo-5-formylthiazole (100.6 mg, 0.524 mmol)in THF (5 mL) was added MeMgBr (175 μL of a 3M solution in Et₂O, 0.524mmol). After 30 minutes, additional MeMgBr (50 μL of a 3M solution inEt₂O, 0.150 mmol) was added. After 30 more minutes, the reaction wasquenched by pouring into saturated NH₄Cl (20 mL). The mixture wasextracted with EtOAc (50 mL) and the organic layer was washed with waterand brine (25 mL each). The organic layer was dried over Na₂SO₄,filtered, and concentrated. Purification of the residue by flashchromatography (0 to 80% EtOAc/hexanes) afforded1-(2-bromo-1,3-thiazol-5-yl)ethanol. R_(f)=0.13 (25% EtOAc/hexanes).LCMS=210.0 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.40 (s, 1H), 5.12 (q,J=6.4 Hz, 1H), 1.59 (d, J=6.4 Hz, 3H).

4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-iodo-1,3-thiazole Step A:4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-thiazole

To a solution of 1,3-thiazol-4-ylmethanol (311.4 mg, 2.7 mmol) in CH₂Cl₂(15 mL) was added Et₃N (1.9 mL, 13.6 mmol). The solution was cooled to−78° C. and TBSOTf (776 μL, 3.38 mmol) was added. The reaction waswarmed to room temperature and stirred for 1 hour. Next, the reactionwas diluted with EtOAc (75 mL) and washed with saturated NaHCO₃, brine,1N HCl, and brine (20 mL each). The organic layer was dried over Na₂SO₄,filtered, and concentrated. The residue was purified by flashchromatography on silica gel (0 to 15% EtOAc/hexanes) to afford4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-thiazole. R_(f)=0.28 (15%EtOAc/hexanes). LCMS=230.1 (M+1)⁺. ¹H NMR (CDCl₃, 600 MHz) δ 8.77 (d,J=2.0 Hz, 1H), 7.25 (m, 1H), 4.93 (d, J=1.1 Hz, 2H), 0.95 (s, 9H), 0.12(s, 6H).

Step B: 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-iodo-1,3-thiazole

To a −78° C. solution of4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-thiazole (106.4 mg, 0.465mmol) in THF (5 mL) was added dropwise a solution of n-BuLi (465 μL of a1.6M solution in hexanes, 0.744 mmol). The reaction was stirred at −78°C. for 30 minutes, and then a solution of iodine (295 mg, 1.16 mmol) inTHF (5 mL) was added by cannula. The reaction was warmed to roomtemperature for 15 minutes and then quenched by pouring into aq. NaHSO₃(20 mL). The mixture was extracted with EtOAc (60 mL) and the organiclayer was washed with brine, saturated NaHCO₃, and brine (20 mL each).The organic layer was dried over Na₂SO₄, filtered, and concentrated.Purification of the residue by flash chromatography (15% EtOAc/hexanes)afforded 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-iodo-1,3-thiazole.R_(f)=0.55 (15% EtOAc/hexanes). LCMS=356.0 (M+1)⁺. ¹H NMR (CDCl₃, 600MHz) δ 7.16 (s, 1H), 4.86 (s, 2H), 0.93 (s, 9H), 0.10 (s, 6H).

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one(975 mg, 1.633 mmol) in DMSO (16 mL) were added bis(pinacolato)diboron(1.24 g, 4.899 mmol),[1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complexwith dichloromethane (1:1) (133 mg, 0.1633 mmol), and KOAc (320 mg,3.266 mmol). The mixture was degassed with N₂, and then heated at 80° C.for 16 hours. The reaction was then cooled to room temperature, dilutedwith EtOAc (200 mL), and washed with saturated NaHCO₃ and brine (80 mLeach). The organic layer was dried over Na₂SO₄, filtered through a plugof silica, and concentrated. Purification of the residue byreverse-phase chromatography (C-18, 10 to 95% MeCN/water with 0.1% TFAA)afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one.LCMS=598.1 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.98 (d, J=7.8 Hz, 1H),7.88 (s, 1H), 7.78 (s, 2H), 7.67 (s, 1H), 7.57 (d, J=7.8 Hz, 1H), 5.68(d, J=7.5 Hz, 1H), 5.01 (d, J=15.6 Hz, 1H), 4.76 (d, J=15.5 Hz, 1H),3.98-3.93 (m, 1H), 1.35 (d, J=6.9 Hz, 12H), 0.77 (d, J=6.7 Hz, 3H).

Example 118

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

In a tube were placed(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one(52.5 mg, 0.0879 mmol), 3-isopropylbenzeneboronic acid (17.3 mg, 0.106mmol), DME (370 μL), EtOH (120 μL), and 1M aqueous Na₂CO₃ (264 μL, 0.264mmol). The mixture was degassed with N₂. Next, Pd(PPh₃)₄ (10.2 mg,8.8×10⁻³ mmol) was added and the mixture was degassed again with N₂. Thetube was sealed and heated at 100° C. for two hours. The reaction wasthen cooled to room temperature, diluted with EtOAc (50 mL), and washedwith water and brine (15 mL each). The organic layer was dried overNa₂SO₄, filtered, and concentrated. Purification of the residue by flashchromatography on silica gel (0 to 15% EtOAc/hexanes) afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.29 (15% EtOAc/hexanes). LCMS=590.1 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.85 (s, 1H), 7.72 (s, 1H), 7.68 (s, 2H), 7.64 (d, J=8.0 Hz, 1H),7.44 (d, J=8.0 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H),7.15 (bs, 1H), 7.11 (bd, J=7.5 Hz, 1H), 5.46 (d, J=8.0 Hz, 1H), 4.91 (d,J=15.7 Hz, 1H), 4.21 (d, J=15.8 Hz, 1H), 3.69 (m, 1H), 2.96 (m, 1H),1.26-1.28 (m, 6H), 0.38 (d, J=6.4 Hz, 3H).

Example 119

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-3′-isopropenyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

In a tube was placed(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3′-chloro-4′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one(Example 146) (30.2 mg, 0.0504 mmol), isopropenylboronic acid (27 mg,0.31 mmol), 1,1-bis(di-t-butylphosphino)ferrocene palladium chloride(5.5 mg, 8.4×10⁻³ mmol), THF (350 μL) and 1 M aq. K₂CO₃ (350 mL). Thetube was degassed with nitrogen, sealed, and heated at 100° C. for 5hours. The reaction was then cooled to room temperature, diluted withEtOAc (50 mL) and washed with water and brine (15 mL each). The organiclayer was dried over Na₂SO₄, filtered, and concentrated. Purification ofthe residue by flash chromatography on silica gel (0 to 15%EtOAc/hexanes) afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-3′-isopropenyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.29 (15% EtOAc/hexanes). LCMS=606.2 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.86 (s, 1H), 7.70 (s, 3H), 7.64 (d, J=8.0 Hz, 1H), 7.42 (d,J=8.0 Hz, 1H), 7.23 (dd, J=7.8, 2.0 Hz, 1H), 7.12-7.17 (m, 2H), 5.54 (d,J=8.0 Hz, 1H), 5.28 (s, 1H), 5.26 (s, 1H), 4.90 (d, J=15.8 Hz, 1H), 4.18(d, J=15.8 Hz, 1H), 3.78 (m, 1H), 2.16 (s, 3H), 0.47 (d, J=6.7 Hz, 3H).

Example 120

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1H-pyrrol-3-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one

To a 0° C. solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-{5-(trifluoromethyl)-2-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]benzyl}-1,3-oxazolidin-2-one(Example 149) (22.6 mg, 0.0326 mmol) in THF (2 mL) was added TBAF (65 μLof a 1M solution in THF, 0.065 mmol). After 30 minutes, the reaction wasquenched with saturated NH₄Cl (5 mL). The mixture was extracted withEtOAc (35 mL) and the organic layer was washed with water and brine (15mL each). The organic layer was dried over Na₂SO₄, filtered, andconcentrated. Purification of the residue by flash chromatography onsilica gel (25 to 60% EtOAc/hexanes) afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1H-pyrrol-3-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one.R_(f)=0.11 (25% EtOAc/hexanes). LCMS=537.1 (M+1)⁺. ¹H NMR (CDCl₃, 600MHz) δ 8.49 (s, 1H), 7.85 (s, 1H), 7.71 (s, 2H), 7.64 (s, 1H), 7.58 (d,J=8.1 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 6.88-6.91 (m, 2H), 6.33 (d, J=1.6Hz, 1H), 5.53 (d, J=8.0 Hz, 1H), 5.02 (d, J=15.7 Hz, 1H), 4.46 (d,J=15.6 Hz, 1H), 3.80 (m, 1H), 0.49 (d, J=6.6 Hz, 3H).

Example 121

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1-isopropyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1H-pyrrol-3-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one(6.8 mg, 0.0127 mmol) (Example 120) in DMSO (300 μL) was added powderedKOH (3.6 mg, 0.0643 mmol). After stirring for 15 minutes, 2-iodopropane(3.2 μL, 0.032 mmol) was added. After 1.5 hours of stirring at roomtemperature, water (5 mL) was added, and the mixture was extracted,first with CH₂Cl₂ (2×15 mL) and then with EtOAc (2×15 mL). The combinedorganics were dried over Na₂SO₄, filtered, and concentrated.Purification of the residue by PTLC (25% EtOAc/hexanes) afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1-isopropyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.33 (25% EtOAc/hexanes). LCMS=579.2 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.85 (s, 1H), 7.71 (s, 2H), 7.61 (s, 1H), 7.56 (d, J=8.0 Hz, 1H),7.50 (d, J=8.0 Hz, 1H), 6.83 (t, J=2.1 Hz, 1H), 6.79 (t, J=2.5 Hz, 1H),6.24 (t, J=2.3 Hz, 1H), 5.49 (d, J=8.0 Hz, 1H), 5.04 (d, J=15.5 Hz, 1H),4.48 (d, J=15.6 Hz, 1H), 4.27 (m, 1H), 3.76 (m, 1H), 1.48 (d, J=6.6 Hz,6H), 0.49 (d, J=6.6 Hz, 3H).

Example 122

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-nitro-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one(example 143) (159.4 mg, 0.276 mmol) in HOAc (5 mL) was added HNO₃ (1.5mL). After 45 minutes, additional HNO₃ (1.5 mL) was added. 45 minuteslater, the reaction was quenched by pouring into ice water (30 mL). Themixture was extracted with EtOAc (75 mL), and the organic layer waswashed with 1 N NaOH, saturated NaHCO₃, and brine (25 mL each). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated.Purification of the residue by flash chromatography on silica gel (8 to40% EtOAc/hexanes) afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-nitro-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.11 (25% EtOAc/hexanes). LCMS=623.1 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz, rotamers present) δ 8.34 (m, 1H), 8.10 (m, 1H), 7.85 (d, J=6.9 Hz,1H), 7.61-7.71 (m, 4H), 7.40 (m, 1H), 7.11 (m, 1H), 5.66 (d, J=8.0 Hz),5.28 (d, J=8.2 Hz), 4.89-4.94 (m, 1H), 3.74-4.09 (m, 5H), 0.61 (d, J=6.6Hz), 0.47 (d, J=6.5 Hz).

Example 123

(4S,5R)-3-{[5′-amino-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-nitro-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one(example 122) (48.2 mg, 0.077 mmol) in EtOAc (4 mL) was added PtO₂ (12mg) and the reaction was placed under an atmosphere of hydrogen(balloon) and stirred vigorously. After 45 minutes, the catalyst wasremoved by filtration through a plug of silica gel with 100% EtOAc. Thefiltrate was concentrated to afford(4S,5R)-3-{[5′-amino-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.20 (40% EtOAc/hexanes). LCMS=593.2 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz, rotamers present) δ 7.85 (s, 1H), 7.60-7.70 (m, 4H), 7.36 (d, J=7.8Hz, 1H), 6.74-6.84 (m, 2H), 6.56 (s, 1H), 5.45-5.54 (m, 1H), 4.82-4.87(m, 1H), 3.64-4.17 (m, 2H), 3.70 (s, 3H), 0.43-0.53 (m, 3H).

Example 124

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylthio)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-3-{[5′-amino-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(Example 123) (40 mg, 0.0676 mmol) in CHCl₃ (1 mL) that had beendegassed with N₂ was added methyl disulfide (10 μL, 0.101 mmol) andt-butyl nitrite (16 μL, 0.135 mmol). The reaction was stirred at roomtemperature for 30 minutes and then heated to reflux for 2 hours. Thereaction was then cooled to room temperature and diluted with hexanes (3mL). The solution was loaded directly onto a silica gel column andeluted with 25% EtOAc/hexanes. Fractions containing the desired productwere combined and repurified by silica gel chromatography with 5 to 25%EtOAc/hexanes to afford(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylthio)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.52 (40% EtOAc/hexanes). LCMS=624.1 (M+1)⁺. ¹H NMR (CDCl₃, 600MHz, rotamers present) δ 6.94-7.85 (m, 9H), 5.58 (d, J=8.1 Hz) 5.25 (d,J=7.8 Hz), 4.94 (d, J=15.8 Hz), 4.85 (d, J=15.7 Hz), 3.65-4.12 (m, 5H),2.47 (s), 2.44 (s), 0.54 (d, J=6.6 Hz), 0.40 (d, J=6.6 Hz).

Example 125

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylsulfinyl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

To a −60° C. solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylthio)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one(example 124) (32.5 mg, 0.0522 mmol) in CH₂Cl₂ (5 mL) was added m-CPBA(14.6 mg, 77% purity, 0.0652 mmol). The reaction was warmed slowly to−20° C. and then diluted with EtOAc (35 mL), washed with aq. NaHSO₃,brine, saturated NaHCO₃, and brine (15 mL each). The organic layer wasdried over Na₂SO₄, filtered, and concentrated. Purification of theresidue by flash chromatography on slica gel (20 to 100% EtOAc/hexanes)afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylsulfinyl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.10 (75% EtOAc/hexanes). LCMS=640.1 (M+1)⁺. ¹H NMR (CDCl₃, 600MHz) δ 7.10-7.86 (m, 9H), 4.87-5.59 (m, 2H), 3.56-4.14 (m, 5H), 2.79(s), 2.75 (s), 2.73 (s), 0.61 (d, J=6.5 Hz), 0.57 (d, J=6.4 Hz), 0.46(d, J=6.4 Hz), 0.43 (d, J=6.5 Hz).

Example 126

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylsulfonyl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

To a 0° C. solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylthio)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one(example 124) (7.8 mg, 0.013 mmol) in CH₂Cl₂ (1 mL) was added m-CPBA (14mg, 77% purity, 0.063 mmol). The reaction was stirred at roomtemperature for 30 minutes and then diluted with EtOAc (35 mL), washedwith aq. NaHSO₃, brine, saturated NaHCO₃, and brine (15 mL each). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated.Purification of the residue by PTLC (50% EtOAc/hexanes) afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylsulfonyl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.11 (40% EtOAc/hexanes). LCMS=656.2 (M+1)⁺. ¹H NMR (CDCl₃, 600MHz, rotamers present) δ 7.99-8.02 (m, 1H), 7.84-7.86 (m, 1H), 7.75-7.78(m, 1H), 7.58-7.72 (m, 4H), 7.38-7.42 (m, 1H), 7.15-7.18 (m, 1H), 5.55(d, J=8.0 Hz), 5.26 (d, J=8.1 Hz), 4.91-4.97 (m, 1H), 3.63-4.03 (m, 5H),3.12 (s), 3.10 (s), 0.62 (d, J=6.6 Hz), 0.48 (d, J=6.6 Hz).

Example 127

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(6-isopropenylpyridine-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-oneStep A: 2-bromo-6-isopropenylpyridine

In a tube were placed 2,6-dibromopyridine (100 mg, 0.422 mmol),isopropenylboronic acid (40 mg, 0.464 mmol), DME (1.5 mL), EtOH (500μL), and 1M aqueous Na₂CO₃ (1 mL, 1.0 mmol). The mixture was degassedwith N₂. Next, Pd(PPh₃)₄ (37 mg, 0.032 mmol) was added and the mixturewas degassed again with N₂. The tube was sealed and heated at 100° C.for 1 hour. The reaction was then cooled to room temperature, dilutedwith EtOAc (50 mL), and washed with water and brine (15 mL each). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated.Purification of the residue by flash chromatography on silica gel (5%EtOAc/hexanes) afforded 2-bromo-6-isopropenylpyridine. R_(f)=0.45 (15%EtOAc/hexanes). LCMS=200.0 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.49 (t,J=7.8 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 5.93 (s,1H), 5.32 (m, 1H), 2.17 (s, 3H).

Step B:(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(6-isopropenylpyridine-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

In a tube were placed 2-bromo-6-isopropenylpyridine (17.5 mg, 0.0878mmol),(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one(26.2 mg, 0.0439 mmol), DME (190 μL), EtOH (62 μL), and 1M aqueousNa₂CO₃ (100 μL, 0.1 mmol). The mixture was degassed with N₂. Next,Pd(PPh₃)₄ (9 mg, 7.8×10⁻³ mmol) was added and the mixture was degassedagain with N₂. The tube was sealed and heated at 100° C. for 2 hours.The reaction was then cooled to room temperature, diluted with EtOAc (50mL), and washed with water and brine (15 mL each). The organic layer wasdried over Na₂SO₄, filtered, and concentrated. Purification of theresidue by flash chromatography on silica gel (5 to 25% EtOAc/hexanes)afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(6-isopropenylpyridine-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.15 (15% EtOAc/hexanes). LCMS=589.1 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.81-7.85 (m, 2H), 7.74 (s, 1H), 7.69-7.69 (m, 3H), 7.58 (d,J=8.0 Hz, 1H), 7.53 (d, J=7.7 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H), 5.94 (s,1H), 5.48 (d, J=7.7 Hz, 1H), 5.36 (s, 1H), 5.06 (d, J=16.0 Hz, 1H), 4.47(d, J=16.1 Hz, 1H), 3.91 (m, 1H), 2.23 (s, 3H), 0.50 (d, J=6.6 Hz, 3H).

Example 128

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(3-methoxy-6-methyl-1-oxidopyridin-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To a 0° C. solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(3-methoxy-6-methylpyridin-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one(Example 174) (7.6 mg, 0.0128 mmol) in CH₂Cl₂ (1.3 mL) was added m-CPBA(5.8 mg, 77% purity, 0.0256 mmol). The reaction was stirred at roomtemperature for 1 hour and then diluted with CH₂Cl₂ (10 mL), washed withaq. NaHSO₃, saturated K₂CO₃, and brine (5 mL each). The organic layerwas dried over Na₂SO₄, filtered, and concentrated. Purification of theresidue by PTLC (50% Et₂O/CH₂Cl₂) afforded the title compound.R_(f)=0.23 (50% Et₂O/CH₂Cl₂). LCMS=609.2 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz)δ 7.85 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.70 (s, 2H), 7.62 (s, 1H), 7.53(d, J=7.8 Hz, 1H), 7.32 (d, J=8.9 Hz, 1H), 7.04 (d, J=9.2 Hz, 1H), 5.74(d, J=8.3 Hz, 1H), 4.88 (d, J=14.8 Hz, 1H), 4.11-3.96 (m, 1H), 3.88 (d,J=14.9 Hz, 1H), 3.86 (s, 3H), 2.49 (s, 3H), 0.65 (d, J=6.6 Hz, 3H).

Example 129

(4S,5R)-3-[2-(3-amino-6-isopropylpyridine-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(6-isopropenyl-3-nitropyridin-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one(example 177) (19.3 mg, 0.0305 mmol) in EtOH (300 μL) was added 10% Pd/C(5 mg). The reaction was placed under a H₂ atmosphere (balloon) andstirred vigorously. After 90 minutes, the mixture was loaded on to aPTLC plate and purified (30% EtOAc/hexanes, developed twice), affording(4S,5R)-3-[2-(3-amino-6-isopropylpyridine-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.63 (30% EtOAc/hexanes, developed twice). LCMS=606.2 (M+1)⁺. ¹HNMR (CDCl₃, 500 MHz) δ 7.84 (s, 1H), 7.78 (s, 1H), 7.72 (d, J=8.0 Hz,1H), 7.69 (s, 2H), 7.55 (d, J=8.0 Hz, 1H), 7.09-7.05 (m, 2H), 5.53-5.52(m, 1H), 4.92 (d, J=5.5 Hz, 1H), 4.15-4.10 (m, 1H), 3.89-3.78 (m, 1H),3.48 (s, 2H), 3.00-2.95 (m, 1H), 1.26-1.23 (m, 6H), 0.44 (d, J=5.1 Hz,3H).

Example 130

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(3-chloro-6-isopropylpyridine-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of CuCl₂ (9.3 mg) and t-butyl nitrite (6.6 μL, 0.0559mmol) in MeCN (300 μL) was added(4S,5R)-3-[2-(3-amino-6-isopropylpyridine-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(Example 129) (16.9 mg, 0.0279 mmol) in MeCN (300 μL) via cannula. Thereaction was heated at 60° C. for 1 hour and then cooled to roomtemperature, diluted with EtOAc (20 mL) and washed with water and brine(8 mL each). The organic layer was dried over Na₂SO₄, filtered, andconcentrated. Purification of the residue by PTLC (30% EtOAc/hexanes)afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(3-chloro-6-isopropylpyridine-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.56 (30% EtOAc/hexanes). LCMS=625.1 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.85 (s, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.73-7.71 (m, 2H), 7.68 (s,2H), 7.53 (d, J=7.8 Hz, 1H), 7.24 (d, J=8.2 Hz, 1H), 5.55 (d, J=7.7 Hz,1H), 5.05 (d, J=15.4 Hz, 1H), 3.97 (d, J=15.4 Hz, 1H), 3.88-3.82 (m,1H), 3.17-3.08 (m, 1H), 1.30-1.32 (m, 6H), 0.53 (d, J=6.7 Hz, 3H).

Example 131

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-isopropenyl-1,3-thiazol-4-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-oneStep A: 4-bromo-2-isopropenyl-1,3-thiazole

In a tube were placed 2,4-dibromothiazole (100 mg, 0.411 mmol),isopropenylboronic acid (39 mg, 0.452 mmol), DME (1.625 mL), EtOH (563μL), and 1M aqueous Na₂CO₃ (1.03 mL, 1.03 mmol). The mixture wasdegassed with N₂. Next, Pd(PPh₃)₄ (24 mg, 0.0206 mmol) was added and themixture was degassed again with N₂. The tube was sealed and heated at100° C. for 2 hours. The reaction was then cooled to room temperature,diluted with EtOAc (50 mL), and washed with water and brine (15 mLeach). The organic layer was dried over Na₂SO₄, filtered, andconcentrated. Purification of the residue by flash chromatography onsilica gel (0 to 15% EtOAc/hexanes) afforded4-bromo-2-isopropenyl-1,3-thiazole; NMR showed an impurity present thatwas not removed. R_(f)=0.53 (15% EtOAc/hexanes). LCMS=206.0 (M+1)⁺. ¹HNMR (CDCl₃, 500 MHz) δ 7.13 (s, 1H), 5.87 (s, 1H), 5.33 (d, J=1.3 Hz,1H), 2.21 (s, 3H).

Step B:(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-isopropenyl-1,3-thiazol-4-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

In a tube were placed 4-bromo-2-isopropenyl-1,3-thiazole (20 mg, 0.097mmol),(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one(29.4 mg, 0.0492 mmol), THF (340 μL), 1M aqueous K₂CO₃ (340 μL), and1,1-bis(di-t-butylphosphino)ferrocene palladium chloride (3.2 mg,4.9×10⁻³ mmol). The mixture was degassed with N₂. The tube was sealedand heated at 100° C. for 1.5 hours. The reaction was then cooled toroom temperature, diluted with EtOAc (50 mL), and washed with water andbrine (15 mL each). The organic layer was dried over Na₂SO₄, filtered,and concentrated. Purification of the residue by flash chromatography onsilica gel (5 to 25% EtOAc/hexanes) and then by PTLC (90%CH₂Cl₂/hexanes) afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-isopropenyl-1,3-thiazol-4-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.16 (15% EtOAc/hexanes). LCMS=595.1 (M+1)⁺. ¹H NMR (CD₂Cl₂, 500MHz) δ 7.90 (s, 1H), 7.64-7.76 (m, 5H), 7.38 (s, 1H), 5.89 (s, 1H), 5.60(d, J=8.1 Hz, 1H), 5.37 (d, J=1.2 Hz, 1H), 4.99 (d, J=16.0 Hz, 1H), 4.66(d, J=16.0 Hz, 1H), 3.94 (m, 1H), 2.25 (s, 3H), 0.59 (d, J=6.4 Hz, 3H).

Example 132

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(hydroxymethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To a 0° C. solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one(Example 178) (54.0 mg, 0.0774 mmol) in THF (10 mL) was added TBAF (194μL of a 1M solution in THF, 0.194 mmol). The reaction was stirred at 0°C. for 30 minutes and then quenched by pouring into saturated NH₄Cl (15mL). The mixture was extracted with EtOAc (60 mL) and the organic layerwas washed with water and brine (15 mL each). The organic layer wasdried over Na₂SO₄, filtered, and concentrated. Purification of theresidue by flash chromatography on silica gel (60% EtOAc/hexanes)afforded(4S,5R)-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(hydroxymethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.11 (40% EtOAc/hexanes). LCMS=585.1 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.85 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.70-7.73 (m, 4H), 7.36 (s,1H), 5.52 (d, J=8.0 Hz, 1H), 5.39 (d, J=15.3 Hz, 1H), 4.81 (s, 2H), 4.55(d, J=15.3 Hz, 1H), 3.87 (m, 1H), 0.69 (d, J=6.7 Hz, 3H).

Example 133

2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazole-4-carbaldehyde

To a 0° C. solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(hydroxymethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one(Example 132) (40.9 mg, 0.070 mmol) in CH₂Cl₂ (5 mL) was added DMP (59.4mg, 0.140 mmol). The reaction was warmed to room temperature and stirredfor 45 minutes. Next the reaction was diluted with EtOAc (40 mL) andwashed with 1N NaOH (2×15 mL) and brine (2×15 mL). The organic layer wasdried over Na₂SO₄, filtered, and concentrated. Purification of theresidue by flash chromatography on silica gel (50% EtOAc/hexanes)afforded2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazole-4-carbaldehyde.R_(f)=0.24 (40% EtOAc/hexanes). LCMS=583.1 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 10.09 (s, 1H), 8.33 (s, 1H), 7.87 (s, 2H), 7.82 (d, J=8.2 Hz,1H), 7.79 (s, 2H), 7.72, (d, J=8.1 Hz, 1H), 5.70 (d, J=8.0 Hz, 1H), 5.13(d, J=16.0 Hz, 1H), 4.83 (d, J=16.0 Hz, 1H), 4.23 (m, 1H), 0.75 (d,J=6.6 Hz, 3H).

Example 134

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxyethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To a −40° C. solution of2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazole-4-carbaldehyde(Example 133) (43.9 mg, 0.075 mmol) in Et₂O (7.5 mL) was added MeMgBr(30 μL of a 3M solution in Et₂O, 0.10 mmol). The reaction was monitoredclosely by TLC and additional MeMgBr was added dropwise until nearly allstarting aldehyde was consumed. At this point, the reaction was quenchedby pouring it into saturated NH₄Cl (15 mL). The mixture was extractedwith EtOAc (50 mL) and the organic layer was washed with water and brine(15 mL each). The organic layer was dried over Na₂SO₄, filtered, andconcentrated. Purification of the residue by flash chromatography onsilica gel (5 to 50% EtOAc/hexanes) afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxyethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.17 (40% EtOAc/hexanes). LCMS=599.1 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.70-7.86 (m, 6H), 7.31-7.32 (m, 1H), 5.53-5.55 (m, 1H),5.35-5.41 (m, 1H), 5.06 (m, 1H), 4.57-4.62 (m, 1H), 3.88 (m, 1H),1.61-1.63 (m, 3H), 0.69 (d, J=6.7 Hz, 3H).

Example 135

(4S,5R)-3-[2-(4-acetyl-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

To a 0° C. solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxyethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one(Example 134) (31.0 mg, 0.052 mmol) in CH₂Cl₂ (6 mL) was added DMP (55mg, 0.130 mmol). The reaction was warmed to room temperature and stirredfor 45 minutes. Next, the reaction was diluted with EtOAc (40 mL) andwashed with 1N NaOH (2×15 mL) and brine (2×15 mL). The organic layer wasdried over Na₂SO₄, filtered, and concentrated. Purification of theresidue by flash chromatography on silica gel (40% EtOAc/hexanes)afforded(4S,5R)-3-[2-(4-acetyl-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.26 (40% EtOAc/hexanes). LCMS=597.1 (M+1)⁺. ¹H NMR (CDCl₃, 600MHz) δ 8.27 (s, 1H), 7.89 (s, 1H), 7.77-7.82 (m, 4H), 7.71 (d, J=7.9 Hz,1H), 5.68 (d, J=7.9 Hz, 1H), 5.22 (d, J=16.3 Hz, 1H), 4.85 (d, J=16.4Hz, 1H), 4.08 (m, 1H), 2.70 (s, 3H), 0.71 (d, J=6.6 Hz, 3H).

Example 136

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxy-1-methylethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To a −40° C. solution of(4S,5R)-3-[2-(4-acetyl-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(Example 135) (38.1 mg, 0.064 mmol) in THF/heptanes (1:1, 8 mL) wasadded MeMgBr (21 tit of a 3M solution in Et₂O, 0.07 mmol). Thetemperature was maintained between −40° C. and −20° C. and the reactionwas monitored closely by TLC; additional MeMgBr was added dropwise untilnearly all starting ketone was consumed. At this point, the reaction wasquenched by pouring it into saturated NH₄Cl (15 mL). The mixture wasextracted with EtOAc (50 mL) and the organic layer was washed with waterand brine (15 mL each). The organic layer was dried over Na₂SO₄,filtered, and concentrated. Purification of the residue by flashchromatography on silica gel (10 to 60% EtOAc/hexanes) afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxy-1-methylethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.20 (40% EtOAc/hexanes). LCMS=613 (M+1)⁺. ¹H NMR (CD₂Cl₂, 500MHz) δ 7.90 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.77 (s, 3H), 7.71 (d,J=8.3 Hz, 1H), 7.32 (s, 1H), 5.59 (d, J=8.0 Hz, 1H), 5.28 (d, J=15.8 Hz,1H), 4.74 (d, J=15.8 Hz, 1H), 3.89 (m, 1H), 3.01 (bs, 1H), 1.63 (s, 3H),1.62 (s, 3H), 0.64 (d, J=6.5 Hz, 3H).

Example 137

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(4-isopropenyl-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxy-1-methylethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one(example 136) (9.5 mg, 0.015 mmol) in toluene (4 mL) was addedp-toluenesulfonic acid monohydrate (20 mg, 0.105 mmol). The reaction washeated to 80° C. for 30 minutes and then cooled to room temperature,diluted with EtOAc (35 mL), and washed with saturated NaHCO₃ and brine(15 mL each). The organic layer was dried over Na₂SO₄, filtered, andconcentrated. Purification of the residue by flash chromatography onsilica gel (25% EtOAc/hexanes) afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(4-isopropenyl-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.55 (40% EtOAc/hexanes). LCMS=595.1 (M+1)⁺. ¹H NMR (CD₂Cl₂, 500MHz) δ 7.91 (s, 1H), 7.78-7.83 (m, 4H), 7.68 (d, J=8.5 Hz, 1H), 7.33 (s,1H), 5.95 (d, J=0.9 Hz, 1H), 5.66 (d, J=8.0 Hz, 1H), 5.24 (m, 1H), 5.07(d, J=16.4 Hz, 1H), 5.00 (d, J=16.3 Hz, 1H), 4.03 (m, 1H), 2.17 (s, 3H),0.63 (d, J=6.4 Hz, 3H).

Example 138

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-3′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-3′-isopropenyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one(Example 119) (18.8 mg, 0.031 mmol) in EtOH (4.5 mL) was added 10% Pd/C(15 mg). The reaction was placed under a H₂ atmosphere (balloon) andstirred vigorously. After 45 minutes, the catalyst was removed byfiltration. The filtrate was concentrated, and the residue was purifiedby flash chromatography on silica gel with 15% EtOAc/hexanes. Furtherpurification by PTLC with 75% CH₂Cl₂/hexanes afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-3′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.35 (15% EtOAc/hexanes). LCMS=608.2 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.86 (s, 1H), 7.71 (s, 1H), 7.70 (s, 2H), 7.64 (d, J=8.0 Hz, 1H),7.41 (d, J=8.0 Hz, 1H), 7.15 (m, 1H), 7.08-7.12 (m, 2H), 5.52 (d, J=8.0Hz, 1H), 4.89 (d, J=15.7 Hz, 1H), 4.18 (d, J=15.8 Hz, 1H), 3.76 (m, 1H),3.28 (m, 1H), 1.25-1.29 (m, 6H), 0.42 (d, J=6.4 Hz, 3H).

Example 139

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[5-(1-methoxyethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To a 0° C. solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[5-(1-hydroxyethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one(Example 154) (13.2 mg, 0.0221 mmol) in THF (1 mL) was added NaHMDS(26.5 μL of a 1M solution in THF, 0.0265 mmol) followed by MeI (1 drop).After 1.5 hours, additional NaHMDS (15 μL of a 1M solution in THF, 0.015mmol) and MeI (1 drop) were added to the reaction. The reaction waswarmed to room temperature for 20 minutes and then quenched by pouringinto saturated NH₄Cl (10 mL). The mixture was extracted with EtOAc (35mL) and the organic layer was washed with water and brine (15 mL each).The organic layer was dried over Na₂SO₄, filtered, and concentrated.Purification of the residue by flash chromatography on silica gel (15 to75% EtOAc/hexanes) afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[5-(1-methoxyethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.37 (40% EtOAc/hexanes). LCMS=613.0 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.87 (s, 1H), 7.74-7.82 (m, 5H), 7.67 (d, J=8.0 Hz, 1H),6.63-5.66 (m, 1H), 5.08-5.14 (m, 1H), 4.83-4.88 (m, 1H), 4.64-4.68 (m,1H), 4.01-4.08 (m, 1H), 3.34 (m, 3H), 1.60 (d, J=6.4 Hz, 3H), 0.69 (d,J=6.7 Hz, 3H).

Examples 140 and 141

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1-oxido-1-benzothien-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-oneand(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1,1-dioxido-1-benzothien-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-3-[2-(1-benzothien-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(Example 150) (14.5 mg, 0.024 mmol) in CH₂Cl₂ (2 mL) was added m-CPBA(16 mg, 77% purity, 0.071 mmol). The reaction was stirred at roomtemperature for 3 hours, and then diluted with EtOAc (40 mL) and washedwith aq. NaHSO₃ (15 mL), saturated NaHCO₃ (15 mL) and brine (15 mL). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated.Purification of the residue by PTLC (25% EtOAc/hexanes, 2 elutions)afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1,1-dioxido-1-benzothien-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-oneand 2.2 mg (15%) of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1-oxido-1-benzothien-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one.Data for 141: R_(f)=0.09 (25% EtOAc/hexanes). LCMS=636.2 (M+1)⁺. ¹H NMR(CDCl₃, 500 MHz) δ 7.96 (d, J=8.0 Hz, 1H), 7.83 (s, 1H), 7.68-7.77 (m,5H), 7.63 (m, 1H), 7.57 (m, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.28 (s, 1H),5.75 (d, J=8.0 Hz, 1H), 5.21 (d, J=15.8 Hz, 1H), 4.21 (d, J=15.8 Hz,1H), 4.01 (m, 1H), 0.70 (d, J=6.7 Hz, 3H). Data for 140: R_(f)=0.06 (25%EtOAc/hexanes). LCMS=620.2 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.15-7.95(m, 11H), 5.72-5.75 (m, 1H), 5.36 (d, J=15.6 Hz), 5.07 (d, J=15.8 Hz),4.41 (d, J=16.0 Hz), 4.22 (d, J=15.8 Hz), 3.88-4.08 (m, 1H), 0.68 (d,J=6.6 Hz), 0.61 (d, J=6.6 Hz).

Example 142

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethoxy)biphenyl-2-yl]-methyl}-4-methyl-1,3-oxazolidin-2-oneStep A: 2-(bromomethyl)-1-nitro-4-(trifluoromethoxy)benzene

Fuming nitric acid (5 mL) was cooled to 0° C. and3-(trifluoromethoxy)benzyl bromide (1 mL, 6.16 mmol) was added. After 15minutes, the reaction was poured into ice water (100 mL) and extractedwith EtOAc (200 mL). The organic layer was washed with water, saturatedNaHCO₃, and brine (75 mL each). The organic layer was dried over Na₂SO₄,filtered, and concentrated. Purification of the residue by flashchromatography on silica gel (0 to 15% EtOAc/hexanes) afforded2-(bromomethyl)-1-nitro-4-(trifluoromethoxy)benzene R_(f)=0.54 (15%EtOAc/hexanes). ¹H NMR (CDCl₃, 500 MHz) δ 8.14 (d, J=8.9 Hz, 1H), 7.43(m, 1H), 7.31 (m, 1H), 4.82 (s, 2H).

Step B:(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-nitro-5-(trifluoromethoxy)benzyl]-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(840 mg, 2.68 mmol) in DMA (25 mL) was added NaHMDS (2.68 mL of a 1Msolution in THF, 2.68 mmol). The reaction was stirred at roomtemperature for 5 minutes, and then2-(bromomethyl)-1-nitro-4-(trifluoromethoxy)benzene (967 mg, 3.22 mmol)was added by cannula in DMA (5 mL). After 15 minutes, the reaction waspoured into saturated NH₄Cl (50 mL). The mixture was extracted withEtOAc (150 mL) and the organic layer was washed with water and brine (40mL each). The organic layer was dried over Na₂SO₄, filtered, andconcentrated. Purification of the residue by flash chromatography onsilica gel (5 to 25% EtOAc/hexanes) afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-nitro-5-(trifluoromethoxy)benzyl]-1,3-oxazolidin-2-one.R_(f)=0.10 (15% EtOAc/hexanes). LCMS=533.2 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 8.16 (d, J=8.9 Hz, 1H), 7.92 (s, 1H), 7.80 (s, 2H), 7.44 (s, 1H),7.33 (d, J=8.9 Hz, 1H), 5.78 (d, J=7.8 Hz, 1H), 4.94 (d, J=17.0 Hz, 1H),4.79 (d, J=16.9 Hz, 1H), 4.25 (m, 1H), 0.81 (d, J=6.7 Hz, 3H).

Step C:(4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-nitro-5-(trifluoromethoxy)benzyl]-1,3-oxazolidin-2-one(1.07 g, 2.01 mmol) in EtOAc (30 mL) was added PtO₂ (100 mg, 0.44 mmol).The reaction was placed under a H₂ atmosphere (balloon) and stirredvigorously. After 1 hour, the catalyst was removed by filtration, andthe filtrate was concentrated. Purification of the residue by flashchromatography (5 to 40% EtOAc/hexanes) afforded(4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.45 (40% EtOAc/hexanes). LCMS=503.2 (M+1)⁺. ¹H NMR (CDCl₃, 600MHz) δ 7.89 (s, 1H), 7.75 (s, 2H), 7.03 (dd, J=8.7, 2.0 Hz, 1H), 6.90(d, J=2.1 Hz, 1H), 6.67 (d, J=8.7 Hz, 1H), 5.67 (d, J=8.5 Hz, 1H), 4.73(d, J=15.4 Hz, 1H), 4.35 (bs, 2H), 4.09 (d, J=15.4 Hz, 1H), 4.04 (m,1H), 0.78 (d, J=6.6 Hz, 3H).

Step D:(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(582 mg, 1.16 mmol) in CHCl₃ (35 mL) was added t-butyl nitrite (275 μL,2.32 mmol). After 10 minutes, I₂ (736 mg, 2.9 mmol) was added. Thereaction was stirred at room temperature for 30 minutes, and then heatedto 65° C. for 2 hours. The reaction was then cooled to room temperature,diluted with EtOAc (150 mL) and washed with aqueous NaHSO₃, water,brine, saturated NaHCO₃, and brine (50 mL each). The organic layer wasdried over Na₂SO₄, filtered, and concentrated. Purification of theresidue by flash chromatography on silica gel (2 to 15% EtOAc/hexanes)afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.30 (15% EtOAc/hexanes). LCMS=614.1 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.89-7.91 (m, 2H), 7.79 (s, 2H), 7.23 (m, 1H), 6.95 (m, 1H), 5.75(d, J=8.0 Hz, 1H), 4.81 (d, J=15.8 Hz, 1H), 4.32 (d, J=15.8 Hz, 1H),4.07 (m, 1H), 0.78 (d, J=6.6 Hz, 3H).

Step E:(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethoxy)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

In a microwave tube were placed(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one(41.6 mg, 0.0679 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronicacid (18 mg, 0.085 mmol), DME (305 μL), EtOH (100 μL), and 1M aqueousNa₂CO₃ (140 μL, 0.140 mmol). The mixture was degassed with N₂. Next,Pd(PPh₃)₄ (4 mg, 3.4×10⁻³ mmol) was added and the mixture was degassedagain with N₂. The tube was sealed and irradiated in a microwave for 10minutes at 150° C. and 200 W. The reaction was then cooled to roomtemperature, diluted with EtOAc (40 mL), and washed with water and brine(15 mL each). The organic layer was dried over Na₂SO₄, filtered, andconcentrated. Purification of the residue by flash chromatography onsilica gel (2 to 15% EtOAc/hexanes) afforded(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethoxy)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.24 (15% EtOAc/hexanes). LCMS=654.3 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz, rotamers present) δ 7.85 (s, 1H), 7.69 (s, 2H), 7.21-7.30 (m, 4H),6.95-7.00 (m, 1H), 6.65-6.68 (m, 1H), 5.59 (d, J=8.0 Hz), 5.41 (d, J=8.0Hz), 4.74-4.81 (m, 1H), 3.75-4.09 (m, 5H), 3.19 (m, 1H), 1.16-1.27 (m,6H), 0.51 (d, J=6.7 Hz), 0.36 (d, J=6.6 Hz).

Following the general procedures outlined above, the compounds in Table6 were prepared:

TABLE 6

Example A³ LCMS (M + 1)⁺ 143

578.1 144

596.1 145

566.1 146

600.1 147

582.2 148

600.1 149

693.3 150

604.2 151

604.2 152

637.2 153

593.2 154

599.1 155

617.1 156

612.2 157

549.3 158

549.2 159

550.2 160

550.4 161

563.3 162

563.3 163

563.4 164

583.1 165

563.2 166

579.2 167

563.2 168

567.2 169

583.1 170

618.1 171

583.1 172

585.2 173

597.2 174

593.2 175

619.2 176

631.1 177

634.1 178

699.2 179

597.1 180

613.1 181

595.1 182

591.2 183

597.1 184

597.1 185

597.1 186

621.2 187

639.2 188

620.2 189

636.2

Following the general procedures outlined above, the compounds in Table7 were prepared:

TABLE 7

Example A³ A² LCMS (M + 1)⁺ 190

586.3 191

566.1 192

554.3 193

554.3 194

632.2 195

640.2

[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol

A mixture of [2-iodo-5-(trifluoromethyl)phenyl]methanol (EXAMPLE 69)(3.09 g, 10.2 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid(4.34 g, 20.5 mmol), (Ph₃P)₄Pd (1.42 g, 1.23 mmol) and Na₂CO₃ (9.11 g,85.9 mmol) in benzene/EtOH/H₂O (7:1:3, 250 mL) was heated at reflux for24 h under N₂. After cooling to room temperature, the aqueous phase wasseparated and extracted with CH₂Cl₂ (3×50 mL). The combined organiclayers were dried (Na₂SO₄) and concentrated in vacuo to give the crudeproduct. This was purified by flash chromatography (Si, 65×200 mm, 0-20%EtOAc in hexanes gradient) to afford4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol.R_(f)=0.50 (20% EtOAc in hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.86 (s,1H), 7.59 (d, J=6.7 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 6.99 (d, J=8.6 Hz,1H), 6.68 (d, J=12.0 Hz, 1H), 4.52 (br s, 1H), 4.46 (br s, 1H), 3.73 (s,3H), 3.25-3.17 (m, 1H), 1.82 (br s, 1H), 1.24 (d, J=6.8 Hz, 6H).

2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl

A solution of triphenylphosphine (3.11 g, 11.8 mmol) in dry CH₂Cl₂ (7mL) was added by cannula to a stirred solution of carbon tetrabromide(3.93 g, 11.8 mmol) and4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol(3.38 g, 9.87 mmol) in dry CH₂Cl₂ (56 mL) at 0° C. under N₂. Thereaction was allowed to warm to room temperature. After 2 h, thereaction mixture was concentrated in vacuo to give the crude product.This was purified by flash chromatography (Si, 65×200 mm, 0-20% EtOAc inhexanes gradient) to afford2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl.¹H NMR (500 MHz, CDCl₃) δ 7.83 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.35 (d,J=8.0 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 6.72 (d, J=12.0 Hz, 1H), 4.43 (brd, J=10.0 Hz, 1H), 4.30 (br d, J=10.2 Hz, 1H), 3.76 (s, 3H), 3.30-3.22(m, 1H), 1.29 (d, J=6.9 Hz, 6H).

5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4,4-dimethyl-1,3-oxazolidin-2-oneStep A: benzyl{2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate

N-Methylmorpholine (682 mg, 741 μL, 6.74 mmol) and isobutylchloroformate(460 mg, 441 μL, 3.37 mmol) were added successively to a stirredsolution of N-carbobenzyloxy-2-methylalanine (0.64 g, 2.69 mmol) in dryCH₂Cl₂ at 0° C. under N₂. The resulting cloudy mixture was stirred at 0°C. for 90 min. N,O-Dimethylhydroxylamine hydrochloride (316 mg, 3.24mmol) was added portionwise and the mixture was warmed to roomtemperature and stirred for 3 h. The mixture was poured into 1N HCl (30mL) and extracted with CH₂Cl₂ (3×40 mL). The combined extracts werewashed with 1N HCl (30 mL), dried (Na₂SO₄) and concentrated in vacuo togive the crude product. This was purified by flash chromatography (Si,40×160 mm, 0-80% EtOAc in hexanes gradient) to afford benzyl{2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate. R_(f)=0.47(50% EtOAc in hexanes). LCMS calc.=303.1; found=303.2 (M±Na)⁺. ¹H NMR(500 MHz, CDCl₃) δ 7.37-7.29 (m, 5H), 5.82 (s, 1H), 5.09 (s, 2H), 3.60(s, 3H), 3.18 (s, 3H), 1.60 (s, 6H).

Step B: benzyl (1,1-dimethyl-2-oxoethyl)carbamate

Diisobutylaluminum hydride (1.77 mL, 1M solution in toluene, 0.708 mmol)was added to a stirred solution of benzyl{2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate (198.5 mg,0.708 mmol) in dry THF (7.1 mL) at −78° C. under N₂. The reaction wasstirred at −78° C. for 4 h. MeOH (100 mL) and 1N HCl (250 μL) were addedand the reaction was allowed to warm to room temperature. The mixturewas diluted with Et₂O (50 mL) and washed with 1N HCl (2×50 mL), 50%saturated NaHCO₃ (50 mL) and water (50 mL), then dried (MgSO₄) andconcentrated in vacuo to give benzyl (1,1-dimethyl-2-oxoethyl)carbamate.R_(f)=0.40 (20% EtOAc in hexanes). LCMS calc.=244.1; found=244.1(M+Na)⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.43 (s, 1H), 7.38-7.30 (m, 5H), 5.34(s, 1H), 5.09 (s, 2H), 1.37 (s, 6H).

Step C: benzyl{2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate

Ethylmagnesium bromide (1.63 mL, 1M in THF, 1.63 mmol) was addeddropwise to a stirred solution of 1-iodo-3,5-bis(trifluoromethyl)benzene(608 mg, 317 μL, 1.79 mmol) in dry THF (1 mL) at room temperature underN₂ and the reaction was stirred for 30 min. The resulting solution wasadded to a stirred solution of benzyl (1,1-dimethyl-2-oxoethyl)carbamate(163.5 mg, 0.739 mmol) in dry THF (1 mL) at −20° C. and the reaction wasallowed to warm to room temperature over 3 h. Saturated NH₄Cl (10 mL)and water (10 mL) were added and the mixture was extracted with EtOAc(3×20 mL). The combined extracts were dried (Na₂SO₄) and concentrated invacuo to give the crude product. This was purified by flashchromatography (Si, 25×160 mm, 0-40% EtOAc in hexanes gradient) toafford benzyl{2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate.R_(f)=0.40 (20% EtOAc in hexanes). LCMS calc.=436.1; found=436.0 (M+1)⁺.¹H NMR (600 MHz, CDCl₃) δ 7.80 (s, 1H), 7.77 (s, 2H), 7.39-7.33 (m, 5H),5.12-5.08 (m, 2H), 1.36 (s, 1H), 4.90 (d, J=4.4 Hz, 1H), 4.81 (s, 1H),1.36 (s, 3H), 1.23 (s, 3H).

benzyl [(1S)-2-(4-chloropyridin-2-yl)-1-methyl-2-oxoethyl]carbamate

A solution of 2-(dimethylamino)ethanol (471 mg, 531 mL, 5.28 mmol) indry hexanes (3.3 mL) was cooled to −5° C. and n-butyllithium (1.6 M inhexanes, 6.60 mL, 10.6 mmol) was added dropwise under N₂. After 30 minat 0° C., the solution was cooled to −78° C. and a solution of4-chloropyridine (obtained by washing a solution of the correspondingHCl salt (264 mg, 1.76 mmol) in CH₂Cl₂ (20 mL) with saturated K₂CO₃ (10mL), then back extracting with CH₂Cl₂ (2×20 mL), combining the organiclayers, drying (Na₂SO₄) and concentrating in vacuo) in hexanes (3.3 mL)was added dropwise by cannula. The solution became dark red in color andafter 1 h at −78° C., a solution of the electrophile (prepared by addingisopropylmagnesium chloride (2M in THF, 1.29 mL, 2.59 mmol) to asolution of benzyl{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (702 mg,2.64 mmol) in dry THF (3.5 mL) at −15° C. under N₂ and stirring for 15min) was added by cannula. The reaction was allowed to warm slowly toroom temperature overnight. Water (25 mL) and saturated NH₄Cl (50 mL)were added and the mixture was extracted with EtOAc (3×50 mL). Thecombined extracts were dried (MgSO₄) and concentrated in vacuo to givethe crude product. This was purified by flash chromatography (Si, 40×160mm, 0-30% EtOAc in hexanes gradient) to afford benzyl[(1S)-2-(4-chloropyridin-2-yl)-1-methyl-2-oxoethyl]carbamate. R_(f)=0.46(20% EtOAc in hexanes). LCMS calc.=319.1; found=319.3 (M+1)⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.58 (d, J=5.0 Hz, 1H), 8.04 (s, 1H), 7.47 (dd,J=5.2, 2.0 Hz, 1H), 7.35-7.30 (m, 5H), 5.78 (s, 1H), 5.72 (m, 1H), 5.11(m, 2H), 1.47 (d, J=7.0 Hz, 3H).

benzyl [(1S)-1-methyl-2-oxo-2-(1,3-thiazol-2-yl)ethyl]carbamate

n-Butyllithium (1.6M in hexanes, 1.76 mL, 2.83 mmol) was added dropwiseto a stirred solution of 2-bromothiazole (462 mg, 251 μL, 2.82 mmol) indry THF (13 mL) at −78° C. under N₂ and the reaction was stirred at −78°C. for 45 min. Separately, isopropylmagnesium chloride (2M in THF, 0.94mL, 1.99 mmol) was added to a stirred solution of benzyl{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (500 mg,1.88 mmol) in dry THF (4 mL) at −15° C. under N₂. This solution wasstirred for 15 min at −15° C. and was added dropwise to the above2-lithiothiazole solution at −78° C. The reaction was allowed to warm toroom temperature overnight and saturated NH₄Cl (20 mL) and water (10 mL)were added and the mixture was extracted with EtOAc (3×30 mL). Thecombined extracts were washed with brine, dried (Na₂SO₄) andconcentrated in vacuo to give the crude product. This was purified byflash chromatography (Si, 25×160 mm, 0-50% EtOAc in hexanes gradient) toafford benzyl [(1S)-1-methyl-2-oxo-2-(1,3-thiazol-2-yl)ethyl]carbamate.R_(f)=0.28 (20% EtOAc in hexanes). LCMS calc.=291.1; found=291.3 (M+1)⁺.¹H NMR (600 MHz, CDCl₃) δ 8.03 (s, 1H), 7.70 (d, J=3.1 Hz, 1H),7.34-7.29 (m, 5H), 5.79 (d, J=6.6 Hz, 1H), 5.53-5.49 (m, 1H), 5.14-5.08(m, 2H), 1.55 (d, J=6.4 Hz, 3H).

Benzyl [(1S)-1-methyl-2-(1-methyl-1H-imidazol-4-yl)-2-oxoethyl]carbamate

A solution of benzyl{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (64 mg,0.24 mmol) in CH₂Cl₂ (1 mL) was cooled to −20° C. under N₂, andisopropylmagnesium chloride (120 μL of a 2.0 M solution in THF) wasadded dropwise. The mixture was stirred at −20° C. for 20 min. In aseparate flask ethylmagnesium bromide (480 μL of a 2.0 M solution inEt₂O) was added to a solution of 4-iodo-1-methyl-1-H-imidazole (109 mg,0.48 mmol) in dry CH₂Cl₂ (1.5 mL) at room temperature. The resultingmixture was stirred for 20 min and then added by cannula to the solutionabove slowly. The resulting solution was left to stir overnight.Saturated NH₄Cl was added to the reaction solution. The mixture wasdiluted with water and the aqueous phase was extracted with CH₂Cl₂ (2×25mL). The combined organic extracts were dried (Na₂SO₄) and concentratedin vacuo. Flash chromatography of the residue yielded benzyl[(1S)-1-methyl-2-(1-methyl-1H-imidazol-4-yl)-2-oxoethyl]carbamate. LCMScalc.=288.14; found=288.3 (M+1)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.65 (s,1H); 7.47 (s, 1H); 7.35-7.28 (m, 5H); 5.93 (d, J=6.9 Hz, 1H); 5.29-5.25(m, 1H); 5.13 (s, 2H); 3.73 (s, 3H); 1.26 (d, J=7.1 Hz, 3H).

Benzyl((1S)-2-{1-[(benzyloxy)methyl]-1H-imidazol-2-yl}-1-methyl-2-oxoethyl)carbamateStep A: 1-[(benzyloxy)methyl]-1H-imidazole

A mixture of chloromethylether (4.3 mL, 29 mmol) and imidazole (6 g, 58mmol) in acetonitrile (200 mL) was heated at reflux for 3.5 h. Thesolvent was removed in vacuo. The resulting oily residue was partitionedbetween CH₂Cl₂ (300 mL) and water (150 mL). Then the organic extract waswashed with water (2×150 mL), dried (Na₂SO₄) and concentrated in vacuoto yield 1-[(benzyloxy)methyl]-1H-imidazole used without furtherpurification. LCMS calc.=189.10; found=189.1 (M+1)⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.63 (s, 1H); 7.40-7.30 (m, 5H); 7.16 (t, J=6.5 Hz, 1H); 7.09(t, J=10.6 Hz, 1H); 5.34 (s, 2H); 4.45 (s, 2H).

Step B: benzyl((1S)-2-{1-[(benzyloxy)methyl}-1H-imidazol-2-yl]-1-methyl-2-oxoethyl)carbamate

To a solution of 1-[(benzyloxy)methyl]-1H-imidazole (706 mg, 3.75 mmol)in THF (4 mL) at −78° C. under N₂, was added n-Butyllithium (2.3 mL of a1.6 M solution in hexanes). The mixture was stirred at −78° C. for 30min. To a solution of benzyl{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (200 mg,0.75 mmol) in THF (2 mL) under N₂ at −15° C., was addedisopropylmagnesium chloride (375 μL of a 2.0 M solution in THF). Theresulting mixture was stirred at −15° C. for 15 min. This mixture wasthen added, by cannula to the solution above at −78° C. The mixturestirred at −78° C. for about 3 h, then warmed up gradually to roomtemperature and stirred overnight. The mixture was quenched withsaturated NH₄Cl. The aqueous layer was extracted with CH₂Cl₂ (3×25 mL).The organic layers were combined, dried (Na₂SO₄) and concentrated invacuo. The residue was purified by flash chromatography to afford benzyl((1S)-2-{1-[(benzyloxy)methyl]-1H-imidazol-2-yl}-1-methyl-2-oxoethyl)carbamatecontaminated with about 30% of the unreacted starting material benzyl{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate. Themixture was carried forward to the next step without furtherpurification. LCMS calc.=394.18; found=394.2 (M+1)⁺.

2-bromo-4,5-dichloro-1-methyl-1H-imidazole

A mixture of 2-bromo-4,5-dichloroimidazole (1 g, 4.6 mmol), methyliodide (346 μL, 5.56 mmol), potassium carbonate (1.27 g, 9.2 mmol) andtetrabutylammonium bromide (148 mg, 0.46 mmol) in acetonitrile (2 mL)was stirred vigorously at 70-80° C. for 1.0 h. After cooling to roomtemperature, the inorganic salts were filtered off and washed withacetonitrile. The filtrate was evaporated and the residue was purifiedby flash chromatography (Si) to afford2-bromo-4,5-dichloro-1-methyl-1H-imidazole as a white solid. LCMScalc.=230.89; found=230.9 (M+1)⁺. ¹H NMR (500 MHz, CDCl₃) δ 3.61 (s,3H).

4-iodo-1-methyl-1H-pyrazole

To a solution of 18-crown-6 (132 mg, 0.5 mmol) in Et₂O (8 mL) under N₂,was added potassium tert-butoxide (616 mg, 5.5 mmol). The mixture wasstirred while 4-iodopyrazole (1 g, 5 mmol) was introduced in a singleportion at room temperature. The reaction was cooled to 0° C. and asolution of iodomethane (342 μL, 5.5 mmol) in Et₂O (2 mL) was addeddropwise at 0° C. The resulting mixture was warmed to room temperatureand stirred overnight. The reaction was then diluted with water andextracted with Et₂O (2×50 mL). The combined organic layers were washedwith brine (45 mL), dried over anhydrous Na₂SO₄ and concentrated invacuo. Flash chromatography gave 4-iodo-1-methyl-1H-pyrazole. LCMScalc.=208.96; found=209.0 (M+1)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.52 (s,1H); 7.43 (s, 1H); 3.95 (s, 3H).

3-iodo-1-methyl-1H-pyrazole

1-methyl-1-H-pyrazole-3-amine (250 mg, 2.57 mmol) was heated at refluxfor 3 h with tert-butylnitrile (336 μL, 2.83 mmol) in diiodomethane (5mL). The solvent and volatile material was removed in vacuo and theresulting residue was purified by flash chromatography (Si) to yield3-iodo-1-methyl-1H-pyrazole. LCMS calc.=208.96; found=209.0 (M+1)⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.21 (d, J=2.1 Hz, 1H); 6.42 (d, J=2.2 Hz, 1H);3.94 (s, 3H).

(4S,5S)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-(1-methyl-1H-tetrazol-5-yl)-1,3-oxazolidin-2-oneand(4S,5S)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-(2-methyl-2H-tetrazol-5-yl)-1,3-oxazolidin-2-oneStep A: benzyl[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(1H-tetrazol-5-yl)ethyl]carbamateand benzyl[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(2H-tetrazol-5-yl)ethyl]carbamate

A mixture of benzyl((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyano-1-methylethyl)carbamate(106.6 mg, 0.306 mmol), triethylamine hydrochloride (211 mg, 1.53 mmol)and sodium azide (99.4 mg, 1.56 mmol) in dry toluene (6 mL) was heatedat relux under N₂ for 20 h and at room temperature for 2 days. Thereaction was diluted with 1N HCl (20 mL) and extracted with EtOAc (3×20mL). The combined extracts were dried (Na₂SO₄) and concentrated in vacuoto afford the crude product. This was carried forward with no furtherpurification. LCMS calc.=392.2; found=392.1 (M+1)⁺.

Step B: benzyl[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(1-methyl-1H-tetrazol-5-yl)ethyl]carbamateand benzyl[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(2-methyl-2H-tetrazol-5-yl)ethyl]carbamate

(Trimethylsilyl)diazomethane (2M in hexanes, 459 μL, 0.918 mmol) wasadded dropwise to a solution of the crude benzyl[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(1H-tetrazol-5-yl)ethyl]carbamateand benzyl[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(2H-tetrazol-5-yl)ethyl]carbamatein CH₂Cl₂/MeOH (3:2, 5 mL) at room temperature under N₂. After 15 minand gas evolution had ceased, the reaction mixture was concentrated invacuo to give the crude product. This was purified by flashchromatography (Si, 12×160 mm, 0-70% EtOAc in hexanes gradient) toafford benzyl[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(1-methyl-1H-tetrazol-5-yl)ethyl]carbamateand benzyl[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(2-methyl-2H-tetrazol-5-yl)ethyl]carbamate,as a 2:1 mixture of regioisomers. LCMS calc.=406.2; found=406.2 (M+1)⁺.

Step C: benzyl[(1S,2S)-2-hydroxy-1-methyl-2-(1-methyl-1H-tetrazol-5-yl)ethyl]carbamateand benzyl[(1S,2S)-2-hydroxy-1-methyl-2-(2-methyl-2H-tetrazol-5-yl)ethyl]carbamate

Tetrabutylammonium fluoride (1M, in THF, 177 μL, 0.177 mmol) was addeddropwise to a stirred solution of benzyl[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(1-methyl-1H-tetrazol-5-yl)ethyl]carbamateand benzyl[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(2-methyl-2H-tetrazol-5-yl)ethyl]carbamate(2:1 mixture of regioisomers, 65.2 mg, 0.161 mmol) in THF (2 mL) at 0°C. The reaction was stirred for 2 h at 0° C., diluted with saturatedNH₄Cl (10 mL) and extracted with EtOAc (3×30 mL). The combined extractswere dried (Na₂SO₄) and concentrated in vacuo to give the crude product.This was purified by flash chromatography (Si, 12×160 mm, 0-80% EtOAc inhexanes gradient) to afford benzyl[(1S,2S)-2-hydroxy-1-methyl-2-(2-methyl-2H-tetrazol-5-yl)ethyl]carbamateand benzyl[(1S,2S)-2-hydroxy-1-methyl-2-(1-methyl-1H-tetrazol-5-yl)ethyl]carbamate.2-methyl isomer (INTERMEDIATE 20): LCMS calc.=292.1; found=292.1 (M+1)⁺.¹H NMR (500 MHz, CDCl₃) δ 7.33-7.29 (m, 5H), 5.59 (d, J=8.5 Hz, 1H),5.09-5.00 (m, 5H), 4.49 (m, 1H), 4.26 (s, 3H), 1.07 (d, J=6.9 Hz, 3H).1-methyl isomer (INTERMEDIATE 19): LCMS calc.=292.1; found=292.1 (M+1)⁺.¹H NMR (500 MHz, CDCl₃) δ 7.33-7.29 (m, 5H), 5.72 (s, 1H), 5.07 (m, 3H),4.99 (m, 2H), 4.18 (m, 1H), 4.10 (s, 3H), 1.24 (d, J=6.7 Hz, 3H).

Example 196

(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-methyl}-4-methyl-5-pyridin-4-yl-1,3-oxazolidin-2-oneStep A: benzyl [(1S)-1-methyl-2-oxo-2-pyridin-4-ylethyl]carbamate

A solution of isopropylmagnesium chloride (1.6 mL, 1M in THF, 3.23 mmol)was added dropwise to a stirred solution of benzyl{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (EXAMPLE17, Step 1) (879 mg, 3.30 mmol) in dry THF (4.2 mL) at −15° C. under N₂.The reaction was stirred at −15° C. for 30 min then a suspension of4-pyridylmagnesium bromide in dry THF (prepared by adding ethylmagnesium bromide (6 mL, 2M in THF, 6.00 mmol) to a stirred solution of4-iodopyridine (1.35 g, 6.60 mmol) in dry THF (45 mL) at roomtemperature under N₂ and stirring for 30 min) was added dropwise bycannula. The reaction was allowed to warm to room temperature and wasstirred for 5 h. 1N HCl (15 mL) was added to quench the reaction and themixture was adjusted to basic pH with saturated NaHCO₃. The mixture wasextracted with EtOAc (2×50 mL) and CH₂Cl₂ (3×50 mL). The EtOAc andCH₂Cl₂ extracted were washed with brine separately, dried (Na₂SO₄),combined and concentrated in vacuo to give the crude product. This waspurified by flash chromatography (Si, 40×160 mm, 0-100% EtOAc in hexanesgradient) to afford benzyl[(2R)-1-methyl-2-oxo-2-pyridin-4-ylethyl]carbamate, as a colorlesssolid. R_(f)=0.33 (50% EtOAc/hexanes). LCMS calc.=285.1; found=285.3(M+1)⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.85 (d, J=3.3 Hz, 2H), 7.76 (d, J=5.5Hz, 2H), 7.36-7.32 (m, 5H), 5.70 (d, J=6.8 Hz, 1H), 5.31-5.25 (m, 1H),5.13 (s, 2H), 1.43 (s, 3H).

Step B: benzyl [(1S,2R)-2-hydroxy-1-methyl-2-pyridin-4-ylethyl]carbamate

Lithium tri-tert-butoxyaluminum hydride (964 mg, 3.79 mmol) was added toa solution of benzyl [(2R)-1-methyl-2-oxo-2-pyridin-4-ylethyl]carbamate(539.1 mg, 1.90 mmol) in dry EtOH (40 mL) at −78° C. under N₂. Thereaction was stirred at −78° C. for 2 h. 2% Aqueous acetic acid wasadded to quench the reaction and the mixture was adjusted to basic pHwith saturated NaHCO₃ (˜50 mL). The mixture was extracted with EtOAc(3×100 mL) and the combined extracts were washed with brine (50 mL),dried (Na₂SO₄) and concentrated in vacuo to give the crude product. Thiswas purified by flash chromatography (Si, 40×160 mm, 0-100% EtOAc inhexanes gradient) to afford benzyl[(1S,2R)-2-hydroxy-1-methyl-2-pyridin-4-ylethyl]carbamate as a colorlesssolid. R_(f)=0.49 (EtOAc). LCMS calc.=287.1; found=287.3 (M+1)⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.41 (d, J=5.7 Hz, 2H), 7.36-7.32 (m, 7H), 5.27 (d,J=7.4 Hz, 1H), 5.10 (s, 2H), 4.89 (s, 1H), 4.02 (br s, 1H), 0.96 (d,J=6.7 Hz, 3H).

Step C:(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-pyridin-4-yl-1,3-oxazolidin-2-one

Sodium hydride (52.4 mg, 60% dispersion in mineral oil, 1.31 mmol) wasadded to a solution of benzyl[(1S,2R)-2-hydroxy-1-methyl-2-pyridin-4-ylethyl]carbamate 150 mg, 0.524mmol) in dry THF (6 mL) at room temperature under N₂. After stirring for30 min at room temperature a solution of2-(bromomethyl)-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl (255mg, 0.629 mmol) in dry THF (3 mL) was added by cannula. The reactionmixture was stirred overnight at room temperature. Saturated NH₄Cl (10mL) was added and the mixture was extracted with EtOAc (3×20 mL). Thecombined extracts were dried (Na₂SO₄) and concentrated in vacuo to givethe crude product. This was purified by flash chromatography (Si, 25×160mm, 0-70% EtOAc in hexanes gradient) to afford(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-pyridin-4-yl-1,3-oxazolidin-2-oneas a colorless oil. R_(f)=0.49 (EtOAc). LCMS calc.=503.2; found=503.3(M+1)⁺. ¹H NMR (600 MHz, CDCl₃, 1:1 mixture of atropisomers) δ 8.61 (d,J=4.1 Hz, 2H), 7.68 (s, 0.5H), 7.61 (s, 1H), 7.60 (s, 0.5H), 7.33 (dd,J=7.4, 3.8, Hz 1H), 7.16 (br s, 2H), 6.97 (dd, J=17.8, 8.4 Hz, 1H), 6.67(dd, J=12.0, 3.4 Hz, 1H), 5.44 (d, J=8.2 Hz, 0.5H), 5.28 (d, J=8.0 Hz,0.5H), 4.79 (d, J=15.8 Hz, 0.5H), 4.76 (d, J=15.8 Hz, 0.5H), 4.15-4.09(m, 1H), 3.88 (d, J=15.8 Hz, 0.5H), 3.79-3.70 (m, 0.5H), 3.74 (s, 3H),3.23-3.17 (m, 1H), 1.26-1.16 (m, 6H), 0.52 (d, J=6.5 Hz, 1.5H), 0.38 (d,J=6.5 Hz, 1.5H).

Example 197

(4S,5S)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-(4-methyl-1,3-thiazol-2-yl)-1,3-oxazolidin-2-oneStep A: benzyl [(1S)-1-methyl-2-oxoethyl]carbamate

Dimethylsulfoxide (1.01 g, 918 μL, 12.9 mmol) was added dropwise to astirred solution of oxalyl chloride (790 mg, 543 μL, 6.23 mmol) in dryCH₂Cl₂ (12.6 mL) at −78° C. under N₂ and the reaction was stirred for 15min. A solution of benzyl [(1S)-2-hydroxy-1-methylethyl]carbamate (965mg, 4.61 mmol) in dry CH₂Cl₂ (12.6 mL) was added dropwise by cannula andthe mixture was stirred at −78° C. for 30 min. Triethylamine (1.34 g,1.85 mL, 13.2 mmol) was added and the reaction was allowed to warm toroom temperature and was stirred for 2 h. Water (15 mL) was added andthe aqueous phase was separated and extracted with CH₂Cl₂ (3×15 mL). Thecombined organic extracts were washed with saturated NaHCO₃ and brine,then dried (MgSO₄) and concentrated in vacuo to afford benzyl[(1S)-1-methyl-2-oxoethyl]carbamate as a colorless oil. R_(f)=0.75 (50%EtOAc in hexanes). ¹H NMR (500 MHz, CDCl₃) δ 9.58 (s, 1H), 7.39-7.35 (m,5H), 5.39 (br s, 1H), 5.15 (s, 2H), 4.33 (m, 1H), 1.40 (d, J=7.1 Hz,3H).

Step B: benzyl [(1S)-2-cyano-2-hydroxy-1-methylethyl]carbamate

Diethylaluminum cyanide (4.53 mL, 1M in toluene, 4.53 mmol) was addeddropwise to a stirred solution of benzyl[(1S)-1-methyl-2-oxoethyl]carbamate (0.853 g, 4.12 mmol) in dry toluene(33 mL) at −78° C. under N₂. The mixture was stirred at −78° C. for 6 hand then allowed to warm to room temperature overnight. Saturated NH₄Cl(20 mL) and water (10 mL) were added then the mixture was extracted withEtOAc (3×50 mL). The combined extracts were dried (Na₂SO₄) andconcentrated in vacuo to afford the crude product. This was purified byflash chromatography (Si, 40×160 mm, 0-40% EtOAc in hexanes gradient) toafford benzyl [(1S)-2-cyano-2-hydroxy-1-methylethyl]carbamate as a 3:1mixture of diastereoisomers. R_(f)=0.63 (50% EtOAc in hexanes). LCMScalc.=257.1; found=257.1 (M+1)⁺. ¹H NMR (500 MHz, CDCl₃) majordiastereoisomer: δ 7.39-7.31 (m, 5H), 5.11 (m, 2H), 4.60 br (s, 1H),3.96 (m, 1H), 1.34 (d, J=6.7 Hz, 3H), minor diastereoisomer: δ 7.39-7.31(m, 5H), 5.14 (m, 2H), 4.50 br (s, 1H), 4.10 (m, 1H), 1.30 (d, J=7.0 Hz,3H).

Step C: benzyl((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyano-1-methylethyl)carbamate

tert-Butyldimethylsilyl chloride (471 mg, 3.12 mmol) and imidazole (483mg, 7.10 mmol) were added successively to a stirred solution of benzyl[(1S)-2-cyano-2-hydroxy-1-methylethyl]carbamate (665 mg, 2.84 mmol) indry CH₂Cl₂ (13 mL) at room temperature under N₂ and the mixture wasstirred overnight. Water (30 mL) was added and the mixture was extractedwith Et₂O (3×30 mL). The combined extracts were dried (MgSO₄) andconcentrated in vacuo to give the crude product. This was purified byflash chromatography (Si, 40×160 mm, 0-15% EtOAc in hexanes gradient) toafford benzyl((1S,2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyano-1-methylethyl)carbamateand benzyl((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyano-1-methylethyl)carbamate.(1S,2R)-diastereoisomer: R_(f)=0.29 (10% EtOAc in hexanes). LCMScalc.=349.2; found=349.1 (M+1)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.39-7.33 (m,5H), 5.16 (d, J=12.1 Hz, 1H), 5.07 (d, J=12.1 Hz, 1H), 4.89 (br d, J=6.6Hz, 1H), 4.68 (br, d, 3.6 Hz, 1H), 3.92 (m, 1H), 1.31 (d, J=6.7 Hz, 3H),0.91 (s, 9H), 0.21 (s, 3H), 0.17 (s, 3H). (1S,2S)-diastereoisomer:R_(f)=0.24 (10% EtOAc in hexanes). LCMS calc.=349.2; found=349.1 (M+1)⁺.¹H NMR (500 MHz, CDCl₃) δ 7.38-7.32 (m, 5H), 5.10 (s, 2H), 4.76 (br d,J=6.9 Hz, 1H), 4.63 (br s, 1H), 4.00 (m, 1H), 1.31 (d, J=6.8 Hz, 3H),0.90 (d, J=2.9 Hz, 9H), 0.17 (s, 3H), 0.08 (s, 3H).

Step D: benzyl((1S,2S)-3-amino-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-3-thioxopropyl)carbamate

A mixture of benzyl((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyano-1-methylethyl)carbamate(115.6 mg, 0.287 mmol), diethyldithiophosphate (1 mL) and water (3drops) was stirred overnight at room temperature. The reaction mixturewas partitioned between saturated NaHCO₃ (40 mL) and EtOAc (40 mL). Theaqueous layer was separated and extracted with EtOAc (2×40 mL). Thecombined extracts were dried (Na₂SO₄) and concentrated in vacuo to givethe crude product. This was purified by flash chromatography (Si, 12×160mm, 0-40% EtOAc in hexanes gradient) to afford benzyl((1S,2S)-3-amino-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-3-thioxopropyl)carbamateas a colorless oil. R_(f)=0.30 (20% EtOAc in hexanes). LCMS calc.=383.2;found=383.1 (M+1)⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.36 (s, 1H), 7.87 (s,1H), 7.37-7.29 (m, 5H), 5.13 (m, 2H), 4.85 (d, J=8.2 Hz, 1H), 4.72 (s,1H), 4.47 (m, 1H), 1.05 (d, J=6.7 Hz, 3H), 0.96 (s, 9H), 0.08 (s, 3H),0.07 (s, 3H).

Step E: benzyl[(1S,2S)-2-hydroxy-1-methyl-2-(4-methyl-1,3-thiazol-2-yl)ethyl]carbamate

A solution of benzyl((1S,2S)-3-amino-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-3-thioxopropyl)carbamate(96.8 mg, 0.253 mmol) and chloroacetone (117 mg, 101 μL, 1.27 mmol) indry EtOH (5 mL) was heated at reflux under N₂ for 20 h, then stirred atroom temperature for 2 days. The reaction mixture was concentrated invacuo to give the crude product. This was purified by flashchromatography (Si, 12×160 mm, 0-100% EtOAc in hexanes gradient) toafford benzyl[(1S,2S)-2-hydroxy-1-methyl-2-(4-methyl-1,3-thiazol-2-yl)ethyl]carbamate.R_(f)=0.44 (50% EtOAc in hexanes). LCMS calc.=307.1; found=307.1 (M+1)⁺.¹H NMR (500 MHz, CDCl₃) δ 7.31 (m, 5H), 6.80 (s, 1H), 5.49 (br s, 1H),5.06 (m, 3H), 4.26-4.18 (m, 1H), 2.38 (s, 3H), 1.09 (d, J=6.5 Hz, 3H).

Step F:(4S,5S)-4-methyl-5-(4-methyl-1,3-thiazol-2-yl)-1,3-oxazolidin-2-one

A solution of benzyl[(1S,2S)-2-hydroxy-1-methyl-2-(4-methyl-1,3-thiazol-2-yl)ethyl]carbamate(53.4 mg, 0.174 mmol) in 7.5 N aqueous KOH (1 mL), MeOH, (2 mL) and THF(4 mL) was stirred at room temperature overnight. The reaction mixturewas acidified with 3N HCl and extracted with EtOAc (3×20 mL). Thecombined extracts were washed with brine, dried (Na₂SO₄) andconcentrated in vacuo to afford the product. LCMS calc.=199.1;found=199.1 (M+1)⁺. ¹H NMR (500 MHz, CDCl₃) δ 6.92 (s, 1H), 6.82 (s,1H), 5.91 (d, J=8.2 Hz, 1H), 4.39-4.35 (m, 1H), 2.44 (s, 3H), 0.95 (d,J=6.4 Hz, 3H).

Step G:(4S,5S)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-(4-methyl-1,3-thiazol-2-yl)-1,3-oxazolidin-2-one

Sodium hydride (60% dispersion in mineral oil, 8.1 mg, 0.202 mmol) wasadded to a stirred solution of(4S,5S)-4-methyl-5-(4-methyl-1,3-thiazol-2-yl)-1,3-oxazolidin-2-one(33.4 mg, 0.168 mmol) in dry THF (1 mL) at room temperature under N₂.The reaction was stirred for 15 min then a solution of2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl(81.0 mg, 0.202 mmol) in dry THF (2 mL) was added by cannula. Thereaction was stirred at room temperature overnight. Saturated NH₄Cl (10mL) was added and the mixture was extracted with EtOAc (3×20 mL). Thecombined extracts were dried (Na₂SO₄) and concentrated in vacuo to givethe crude product. This was purified by flash chromatography (Si, 25×160mm, 0-70% EtOAc in hexanes gradient) and chiral HPLC (IA column, 20×250mm, 5% i-PrOH in heptane) to afford(4S,5S)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-(4-methyl-1,3-thiazol-2-yl)-1,3-oxazolidin-2-one.R_(f)=0.18 (20% EtOAc in hexanes). LCMS calc.=523.2; found=523.1 (M+1)⁺.¹H NMR (500 MHz, CDCl₃, 1:1 mixture of atropisomers) δ 7.68 (s, 0.5H),7.63 (s, 0.5H), 7.59 (d, J=8.0 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 6.99 (d,J=8.5 Hz, 0.5H), 6.95 (d, J=8.5 Hz, 0.5H), 6.88 (s, 1H), 6.68 (d, J=5.0Hz, 0.5H), 6.66 (d, J=4.9 Hz, 0.5H), 5.70 (d, J=8.3 Hz, 0.5H), 5.55 (d,J=8.2 Hz, 0.5H), 4.72 (d, J=15.9 Hz, 0.5H), 4.64 (d, J=15.9 Hz, 0.5H),4.20 (d, J=15.9 Hz, 0.5H), 3.95 (d, J=15.9 Hz, 0.5H), 3.91-3.83 (m, 1H),3.75 (s, 1.5H), 3.74 (s, 1.5H), 3.23-3.15 (m, 1H), 2.40 (s, 3H),1.26-1.18 (m, 6H), 0.65 (d, J=6.5 Hz, 1.5H), 0.55 (d, J=6.5 Hz, 1.5H).

Following the general procedures outlined above, the compounds in Table8 were prepared. Example 198 was made as a reference compound.

TABLE 8

Example R LCMS (M + 1)⁺ 198

426.1 199

570.2, 572.1, 574.2 200

520.3 201

516.3 202

536.3 203

532.3 204

570.3 205

586.3 206

527.3 207

527.3 208

548.3 209

545.4 210

588.5 211

546.3 212

538.3 213

554.3 214

538.3 215

554.3 216

562.4 217

556.3 218

584.3 219

624.3 220

652.2 221

508.4 222

494.4 223

503.2 224

503.3 225

503.3 226

503.3 227

508.3 228

508.3 229

542.3, 544.3 230

504.3 231

504.3 232

537.3, 539.3 233

509.2 234

504.4 235

523.1 236

508.1 237

508.1 238

506.4 239

506.3 240

506.2 241

520.3 242

520.3 243

574.1 244

612.3 245

506.2 246

506.2 247

506.2 248

520.2 249

574.2 250

574.2 251

507.2 252

507.2

Example 253, 254

(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-[3-(methylsulfinyl)phenyl]-1,3-oxazolidin-2-one(EXAMPLE 253)(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-[3-(methylsulfonyl)phenyl]-1,3-oxazolidin-2-one(EXAMPLE 254)

To a solution of(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-[3-(methylthio)phenyl]-1,3-oxazolidin-2-one(EXAMPLE 208) (25 mg, 0.0457 mmol) in dry dichloromethane (1.5 mL) underN₂ at 0° C., was added dropwise a solution of 3-chloroperoxybenzoic acid(77%, 26 mg, 0.114 mmol) in CH₂Cl₂ (0.5 mL). After addition the mixturewas left to warm to room temperature and stirred for 2 h. The reactionmixture was quenched with saturated Na₂SO₃ (15 mL). The aqueous layerwas extracted with Et₂O (3×20 mL). The combined organic extracts werewashed with saturated NaHCO₃, dried (Na₂SO₄) and concentrated in vacuo.The crude material was purified by flash chromatography (Si, 12×160 mm,0-60% EtOAc in hexanes gradient) to afford(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-[3-(methylsulfinyl)phenyl]-1,3-oxazolidin-2-oneand(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-[3-(methylsulfonyl)phenyl]-1,3-oxazolidin-2-one.EXAMPLE 253: LCMS calc.=564.19; found=564.3 (M+1)⁺. ¹H NMR (500 MHz,CDCl₃, 1:1 mixture of atropisomers) δ 7.73 (s, 0.5H); 7.66-7.52 (m,4.5H); 7.42 (s, 0.5H); 7.40 (s, 0.5H); 7.37 (d, J=3.4 Hz, 0.5H); 7.36(d, J=3.5 Hz, 0.5H); 7.02 (d, J=8.4 Hz, 0.5H); 6.99 (d, J=8.4 Hz, 0.5H);6.71 (d, J=3.1 Hz, 0.5H); 6.69 (d, J=2.9 Hz, 0.5H); 5.59 (d, J=5.9 Hz,0.5H); 5.57 (d, J=5.9 Hz, 0.5H); 5.42 (t, J=8.4 Hz, 1H); 4.85 (d, J=3.4Hz, 0.5H); 4.82 (d, J=3.4 Hz, 0.5H); 4.80 (d, J=7.8 Hz, 0.5H); 4.77 (d,J=7.7 Hz, 0.5H); 4.16 (d, J=15.8 Hz, 0.5H); 3.92 (d, J=15.8 Hz, 0.5H);3.76 (s, 3H); 3.85-3.72 (m, 1H); 3.26-3.19 (m, 1H); 2.73 (d, J=4.7 Hz,3H); 1.30-1.26 (m, 4.5H); 1.20 (d, J=6.9 Hz, 1.5H); 0.55 (d, J=6.7 Hz,0.75H); 0.52 (d, J=6.7 Hz, 0.75H); 0.41 (d, J=4.0 Hz, 0.75H); 0.39 (d,J=4.1 Hz, 0.75H). EXAMPLE 254: LCMS calc.=580.17; found=580.3 (M+1)⁺. ¹HNMR (500 MHz, CDCl₃, 1:1 mixture of atropisomers) δ 7.95 (s, 0.5H); 7.94(s, 0.5H); 7.81 (s, 0.5H); 7.80 (s, 0.5H); 7.73 (s, 0.5H); 7.65-7.58 (m,3H); 7.57 (s, 0.5H); 7.38 (d, J=3.5 Hz, 0.5H); 7.36 (d, J=3.8 Hz, 0.5H);7.02 (d, J=8.4 Hz, 0.5H); 6.99 (d, J=8.4 Hz, 0.5H); 6.72 (s, 0.5H); 6.69(s, 0.5H); 5.58 (d, J=8.1 Hz, 0.5H); 5.42 (d, J=8.0 Hz, 0.5H); 4.86 (d,J=15.9 Hz, 0.5H); 4.81 (d, J=15.9 Hz, 0.5H); 4.17 (d, J=15.8 Hz, 0.5H);3.91 (d, J=15.8 Hz, 0.5H); 3.81-3.75 (m, 1H); 3.78 (s, 3H); 3.27-3.19(m, 1H); 3.07 (s, 3H); 1.30-1.26 (m, 4.5H); 1.21 (t, J=8.7 Hz, 1.5H);0.53 (d, J=6.5 Hz, 1.5H); 0.39 (d, J=6.5 Hz, 1.5H).

Example 255

3-((4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde

The solution of(4S,5R)-5-[3-(1,3-dioxan-2-yl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one(EXAMPLE 210) (380 mg, 0.647 mmol) in THF and 1N HCl (3:1) (4 mL) wasstirred at room temperature for 2 h. The reaction mixture was dilutedwith EtOAc and washed with NaHCO₃ and brine. The organic layer was driedand concentrated in vacuo. The crude material was purified by flashchromatography (Si) to provide3-((4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde.LCMS calc.=530.19; found=530.4 (M+1)⁺. ¹H NMR (500 MHz, CDCl₃, 1:1mixture of atropisomers) δ 10.03 (s, 1H); 7.88 (s, 0.5H); 7.87 (s,0.5H); 7.77-7.52 (m, 5H); 7.37 (d, J=3.5 Hz, 0.5H); 7.36 (d, J=3.4 Hz,0.5H); 7.02 (d, J=8.4 Hz, 0.5H); 6.99 (d, J=8.4 Hz, 0.5H); 6.71 (d,J=3.5 Hz, 0.5H); 6.69 (d, J=3.4 Hz, 0.5H); 4.17 (d, J=15.8 Hz, 0.5H);6.98 (d, J=15.8 Hz, 0.5H); 3.78 (s, 3H); 3.85-3.71 (m, 1H); 3.26-3.19(m, 1H); 1.30-1.26 (m, 4.5H); 1.19 (d, J=6.9 Hz, 1.5H); 0.53 (d, J=6.6Hz, 1.5H); 0.40 (d, J=6.6 Hz, 1.5H).

Example 256

(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3-(hydroxy)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3-(hydroxy

To a solution of3-((4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde(12 mg, 0.023 mmol) in anhydrous EtOH (1 mL) at 0° C. under N₂, wasadded NaBH₄ (4.5 mg, 0.119 mmol) as a powder. The solution was warmed toroom temperature and stirred for 1 h. The mixture was quenched with 2%HOAc and diluted with water. The aqueous layer was extracted with EtOAc(3×10 mL). The combined organic extracts were washed with saturatedNaHCO₃ (12 mL) and brine (12 mL), dried (Na₂SO₄) and concentrated invacuo. The crude material was purified by flash chromatography to yield(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3-(hydroxy)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3-(hydroxy.LCMS calc.=532.0; found=532.4 (M+1)⁺. ¹H NMR (500 MHz, CDCl₃, 1:1mixture of atropisomers) δ 7.73 (s, 0.5H); 7.67 (s, 0.5H); 7.64 (s,0.5H); 7.62 (s, 0.5H); 7.42-7.32 (m, 3H); 7.24 (s, 1H); 7.15 (s, 0.5H);7.14 (s, 0.5H); 7.01 (d, J=8.4 Hz, 0.5H); 6.98 (d, J=8.5 Hz, 0.5H); 6.71(s, 0.5H); 6.68 (s, 0.5H); 5.51 (d, J=8.1 Hz, 0.5H); 5.37 (d, J=8.0 Hz,0.5H); 4.81 (d, J=15.9 Hz, 0.5H); 4.74 (d, J=16 Hz, 0.5H); 4.73 (s, 2H);4.15 (d, J=15.9 Hz, 1H); 3.92 (d, J=15.9 Hz, 1H); 3.77 (s, 3.0H);3.79-3.74 (m, 0.5H); 3.74-3.68 (m, 0.5H); 3.25-3.18 (m, 1H); 1.29-1.25(m, 4.5H); 1.19 (d, J=6.9 Hz, 1.5H); 0.53 (d, J=6.4 Hz, 1.5H); 0.40 (d,J=6.4 Hz, 1.5H).

Example 257

(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3-(1-hydro)-xyethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of3-((4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde(11 mg, 0.021 mmol) in THF (1 mL) at −78° C. under N₂, was addedmethylmagnesium bromide (30 μL of a 3.0 M solution in Et₂O). The mixturewas stirred at −78° C. for 2 h. The mixture was quenched with saturatedNH₄Cl (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL). Thecombined organic layers were washed with brine (15 mL), dried (Na₂SO₄)and concentrated in vacuo to give the crude product. This was purifiedby flash chromatography (Si) to afford(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3-(1-hydro)-xyethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one.LCMS calc.=546.22; found=546.4 (M+1)⁺. ¹H NMR (500 MHz, CDCl₃, 1:1mixture of atropisomers) δ 7.74 (s, 0.5H); 7.67 (s, 0.5H); 7.64 (s,0.5H); 7.63 (s, 0.5H); 7.36 (m, 3H); 7.24 (s, 1H); 7.15 (s, 0.5H); 7.14(s, 0.5H); 7.01 (d, J=8.5 Hz, 0.5H); 6.99 (d, J=8.5 Hz, 0.5H); 6.71 (s,0.5H); 6.68 (s, 0.5H); 5.52 (d, J=8.0 Hz, 0.5H); 5.36 (d, J=7.9 Hz,0.5H); 4.92 (q, J=6.4 Hz, 1H); 4.83 (d, J=15.7, 0.5H); 4.77 (d, J=16.0,0.5H); 4.16 (d, J=15.5 Hz, 0.5H); 3.92 (d, J=15.5 Hz, 0.5H); 3.77 (d,J=7.1 Hz, 3H); 3.81-3.68 (m, 1H); 3.25-3.18 (m, 1H); 1.64 (br, s, 1H);1.49 (d, J=6.4 Hz, 3H); 1.30-1.26 (m, 4.5H); 1.19 (d, J=6.9 Hz, 1.5H);0.53 (d, J=6.5 Hz, 1.5H); 0.40 (d, J=6.5 Hz, 1.5H).

Following the general procedures outlined above, the compounds in Table9 were prepared:

TABLE 9

Example R LCMS (M + 1)⁺ 258 Et 560.4 259 n-Pr 574.4

Example 260

(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-methyl}-4-methyl-5-{3-[(methylamino)methyl]phenyl}-1,3-oxazolidin-2-one

To a solution of3-((4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde(15 mg, 0.028 mmol) in 1,2-dichloroethane (1 mL) was added methylamine(1 mL of a 2.0 M solution in THF). The resulting mixture was treatedwith sodium triacetoxyborohydride (34.8 mg, 0.16 mmol) and AcOH (0.05mL). The mixture was stirred under N₂ at room temperature for 5 days.The reaction mixture was quenched with 1N NaOH and the aqueous layer wasextracted with ether (3×15 mL). The ether extracts were washed withbrine, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified by flash chromatography (Si) to afford(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-{3-[(methylamino)methyl]phenyl}-1,3-oxazolidin-2-one.LCMS calc.=545.23; found=545.4 (M+1)⁺. ¹H NMR (500 MHz, CDCl₃, 1:1mixture of atropisomers) δ 7.74 (s, 0.5H); 7.67 (s, 0.5H); 7.64 (s,0.5H); 7.62 (s, 0.5H); 7.33 (m, 3H); 7.20 (s, 1H); 7.13 (s, 0.5H); 7.12(s, 0.5H); 7.01 (d, J=8.4 Hz, 0.5H); 6.98 (d, J=8.5 Hz, 0.5H); 6.71 (d,J=2.9 Hz, 0.5H); 6.68 (d, J=2.8 Hz, 0.5H); 5.51 (d, J=8.1 Hz, 0.5H);5.37 (d, J=8.0 Hz, 0.5H); 4.82 (d, J=15.9 Hz, 0.5H); 4.75 (d, J=15.9 Hz,0.5H); 4.16 (d, J=15.9 Hz, 0.5H); 3.92 (d, J=15.9 Hz, 0.5H); 3.77 (m,5.5H); 3.70 (t, J=6.6 Hz, 0.5H); 3.25-3.18 (m, 1H); 2.45 (s, 3H); 1.93(br, s, 1H); 1.27 (m, 4.5H); 1.19 (d, J=6.9 Hz, 1.5H); 0.53 (d, J=6.5Hz, 1.5H); 0.40 (d, J=6.5 Hz, 1.5H).

Example 261

(4S,5R)-5-{3-[(dimethylamino)methyl]-phenyl}-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-methyl}-4-methyl-1,3-oxazolidin-2-one

To a solution of3-((4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde(15 mg, 0.028 mmol) in EtOH (1 mL) was added dimethylamine (140 μL of a2.0 M solution in MeOH) and titanium isopropoxide (79 μL, 0.28 mmol).The resulting white suspension was stirred overnight. Sodium borohydride(7.1 mg, 0.188 mmol) was added and the mixture was stirred overnight.The reaction was quenched by pouring the mixture into 2N aqueous ammonia(2 mL). The resulting inorganic precipitate was filtered and washed withdichloromethane. The combined filtrates were extracted withdichloromethane (2×15 mL). The extracts were dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by flash chromatography(Si) to give(4S,5R)-5-{3-[(dimethylamino)methyl]phenyl}-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.LCMS calc.=559.25; found=559.4 (M+1)⁺. ¹H NMR (500 MHz, CDCl₃, 1:1mixture of atropisomers) δ 7.74 (s, 0.5H); 7.67 (s, 0.5H); 7.64 (s,0.5H); 7.62 (s, 0.5H); 7.37-7.29 (m, 3H); 7.18 (s, 1H); 7.16 (s, 0.5H);7.13 (s, 0.5H); 7.01 (d, J=8.4 Hz, 0.5H); 6.99 (d, J=8.5 Hz, 0.5H); 6.71(d, J=3.0 Hz, 0.5H); 6.68 (d, J=2.9 Hz, 0.5H); 5.52 (d, J=8.1 Hz, 0.5H);5.37 (d, J=8.0 Hz, 0.5H); 4.82 (d, J=15.9 Hz, 0.5H); 4.77 (d, J=16.0 Hz,0.5H); 4.15 (d, J=16.0 Hz, 0.5H); 3.91 (d, J=15.9 Hz, 0.5H); 3.76 (s,3H); 3.80-3.73 (m, 0.5H); 3.72-3.68 (m, 0.5H); 3.43 (s, 2H); 3.25-3.18(m, 1H); 2.23 (s, 6H); 1.27 (m, 4.5H); 1.19 (d, J=6.9 Hz, 1.5H); 0.53(d, J=6.5 Hz, 1.5H); 0.39 (d, J=6.6 Hz, 1.5H).

Example 262

(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-(1H-imidazol-2-yl)-4-methyl-1,3-oxazolidin-2-one

A mixture of(4S,5S)-5-{1-[(benzyloxy)methyl]-1H-imidazol-2-yl}-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one(EXAMPLE 244) (16.9 mg, 0.028 mmol), 20% palladium hydroxide on carbon(8.3 mg) and 1N HCl (28 uL) in MeOH (1 mL) was stirred under hydrogen(balloon) overnight, after which time it was filtered through Celite andconcentrated in vacuo. The crude material was purified by flashchromatography to afford(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-(1H-imidazol-2-yl)-4-methyl-1,3-oxazolidin-2-one.LCMS calc.=492.18; found=492.2 (M+1)⁺. ¹H NMR (500 MHz, CDCl₃, 1:1mixture of atropisomers) δ 7.71 (s, 0.5H); 7.67 (s, 0.5H); 7.65 (s,0.5H); 7.64 (s, 0.5H); 7.37 (d, J=3.2 Hz, 0.5H); 7.35 (d, J=3.3 Hz,0.5H); 7.09 (d, 2H); 7.02 (d, J=8.4 Hz, 0.5H); 6.99 (d, J=8.5 Hz, 0.5H);6.72 (d, J=4.3 Hz, 0.5H); 6.69 (d, J=4.2 Hz, 0.5H); 5.76 (d, J=8.3 Hz,0.5H); 5.64 (d, J=8.7 Hz, 0.5H); 4.72 (d, J=15.8 Hz, 0.5H); 4.68 (d,J=15.8 Hz, 0.5H); 4.20 (d, J=15.7 Hz, 0.5H); 4.01 (d, J=15.7 Hz, 0.5H);3.90 (br, s, 1H); 3.79-3.72 (m, 4H); 3.25-3.18 (m, 1H); 1.28-1.22 (m,6H); 0.67 (d, J=6.5 Hz, 1.5H); 0.59 (d, J=6.5 Hz, 1.5H).

Example 263

(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-methyl}-4-methyl-5-(1-oxidopyridin-4-yl)-1,3-oxazolidin-2-one

m-Chlorobenzoic acid (77%, 47.9 mg, 0.214 mmol) was added to a solutionof(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-pyridin-4-yl-1,3-oxazolidin-2-one(53.7, 0.107 mmol) in dry CH₂Cl₂ (10.8 mL) at 0° C. After 15 min at 0°C., the reaction was stirred at room temperature for 3 h. The reactionwas diluted with CH₂Cl₂ (40 mL) and washed with saturated Na₂SO₃ (20 mL)and saturated K₂CO₃ (2×20 mL). The organic layer was dried (Na₂SO₄) andconcentrated in vacuo to afford(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-(1-oxidopyridin-4-yl)-1,3-oxazolidin-2-oneas an oil. LCMS calc.=519.2; found=519.3 (M+1)⁺.

Example 264

4-((4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)pyridine-2-carbonitrile

Trimethylsilyl cyanide (39.9 mg, 54 μL, 0.402 mmol) was added to astirred solution of(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-(1-oxidopyridin-4-yl)-1,3-oxazolidin-2-one(37.9 mg, 0.0732 mmol) in dry CH₂Cl₂ (2 mL) at room temperature underN₂. The reaction was stirred for 5 min and benzoyl chloride (20.5 mg, 17μL, 0.146 mmol) was added. The reaction was stirred at room temperatureovernight. 50% Saturated K₂CO₃ (10 mL) was added and the mixture wasdiluted with CH₂Cl₂ (20 mL). The aqueous layer was separated andextracted with CH₂Cl₂ (2×10 mL). The combined organic extracts weredried (K₂CO₃) and concentrated in vacuo to give the crude product. Thiswas purified by flash chromatography (Si, 12×160 mm, 0-70% EtOAc inhexanes gradient) to afford the product (11.6 mg, 30%), as a colorlessoil. This was resolved into its enantiomers by chiral HPLC (AD column,20×250 mm, 10% i-PrOH in heptane) to give4-((4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)pyridine-2-carbonitrileand4-((4R,5S)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)pyridine-2-carbonitrile.R_(f)=0.72 (50% EtOAc in hexanes). LCMS calc.=528.2; found=528.3 (M+1)⁺.¹H NMR (500 MHz, CDCl₃, 1:1 mixture of atropisomers) δ 8.73 (s, 1H),7.67-7.59 (m, 2H), 7.55 (d, J=3.3 Hz, 1H), 7.40 (d, J=4.2 Hz, 1H), 7.35(dd, J=7.8, 3.3 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H),6.69 (d, J=3.1 Hz, 1H), 6.67 (d, J=3.1 Hz, 1H), 5.47 (d, J=8.1 Hz,0.5H), 5.30 (d, J=8.1 Hz, 0.5H), 4.81 (t, J=15.1 Hz, 1H), 4.11 (d,J=15.8 Hz, 0.5H), 3.89 (d, J=15.8 Hz, 0.5H), 3.83-3.73 (m, 1H), 3.76 (s,3H), 3.24-3.16 (m, 1H), 1.27-1.17 (m, 6H), 0.54 (d, J=6.5 Hz, 1.5H),0.39 (d, J=6.5 Hz, 1.5H).

Example 265

(4S,5R)-5-(2-chloropyridin-4-yl)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-methyl}-4-methyl-1,3-oxazolidin-2-one

A solution of(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-(1-oxidopyridin-4-yl)-1,3-oxazolidin-2-one(53.7 mg, 0.104 mmol) in phosphorous oxychloride (4 mL) was heated atreflux under N₂ for 2 h. The reaction mixture was cooled to roomtemperature, concentrated in vacuo, diluted with EtOAc (20 mL) and water(5 mL), then washed with saturated NaHCO₃ (10 mL). The aqueous layer wasextracted with EtOAc (2×20 mL). The combined organic layers were dried(Na₂SO₄) and concentrated in vacuo to give the crude product. This waspurified by flash chromatography (Si, 12×160 mm, 0-70% EtOAc in hexanesgradient) to afford the product as a colorless oil. This was resolvedinto its enantiomers by chiral HPLC (AD column, 20×250 mm, 5% i-PrOH inheptane) to afford(4S,5R)-5-(2-chloropyridin-4-yl)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.17 (20% EtOAc in hexanes). LCMS calc.=537.2; found=537.3 (M+1)⁺.¹H NMR (500 MHz, CDCl₃, 1:1 mixture of atropisomers) δ 8.40 (br s, 1H),7.70 (s, 0.5H), 7.63 (s, 1.5H), 7.37 (m, 1H), 7.24 (br s, 1H), 7.10 (brs, 1H), 7.01 (d, J=8.2 Hz, 0.5H), 6.98 (d, J=8.2 Hz, 0.5H), 6.72-6.68(m, 1H), 5.44 (d, J=8.1 Hz, 0.5H), 5.29 (d, J=8.1 Hz, 0.5H), 4.81 (t,J=16.9 Hz, 1H), 4.14 (d, J=15.9 Hz, 0.5H), 3.91 (d, J=15.9 Hz, 0.5H),3.81-3.71 (m, 1H), 3.76 (s, 3H), 3.27-3.19 (m, 1H), 1.29-1.19 (m, 6H),0.58 (d, J=6.5 Hz, 1.5H), 0.44 (d, J=6.5 Hz, 1.5H).

Example 266

(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-(2-methylpyridin-4-yl)-1,3-oxazolidin-2-one

A solution of(4S,5R)-5-(2-chloropyridin-4-yl)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one(20.9 mg, 0.0389 mmol), trimethylboroxin (14.7 mg, 16 μL, 0.116 mmol),Cs₂CO₃ (38.0 mg, 0.117 mmol) and (Ph₃P)₄Pd (9.0 mg, 0.00778 mmol) in dry1,4-dioxane (1 mL) was heated at reflux overnight. The reaction mixturewas filtered through a plug of Celite and washed with EtOAc. Thefiltrate was concentrated in vacuo to afford the crude product. This waspurified by flash chromatography (Si, 12×160 mm, 0-70% EtOAc in hexanesgradient) to afford the product as a colorless oil. This was resolvedinto its enantiomers by chiral HPLC (AD column, 20×250 mm, 10% i-PrOH inheptane) to afford(4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-(2-methylpyridin-4-yl)-1,3-oxazolidin-2-oneand(4R,5S)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-(2-methylpyridin-4-yl)-1,3-oxazolidin-2-one.R_(f)=0.22 (50% EtOAc in hexanes). LCMS calc.=517.2; found=517.1 (M+1)⁺.¹H NMR (500 MHz, CDCl₃, 1:1 mixture of atropisomers) δ 8.48 (d, J=4.9Hz, 1H), 7.69 (s, 0.5H), 7.61 (s, 1H), 7.60 (s, 0.5H), 7.33 (m, 1H),7.05 (s, 1H), 6.99-6.93 (m, 2H), 6.69 (d, J=3.2 Hz, 1H), 6.66 (d, J=3.2Hz, 1H), 5.40 (d, J=8.1 Hz, 0.5H), 5.24 (d, J=8.1 Hz, 0.5H), 4.79 (d,J=15.9 Hz, 0.5H), 4.74 (d, J=15.9 Hz, 0.5H), 4.13 (d, J=15.9 Hz, 0.5H),3.89 (d, J=15.9 Hz, 0.5H), 3.78-3.66 (m, 1H), 3.75 (s, 3H), 3.23-3.17(m, 1H), 2.56 (s, 3H), 1.25-1.17 (m, 6H), 0.53 (d, J=6.5 Hz, 1.5H), 0.39(d, J=6.5 Hz, 1.5H).

Following the general procedures outlined above, the compounds in Table10 were prepared:

TABLE 10

Example R LCMS (M + 1)⁺ 267

519.3 268

537.3, 539.2

Following the general procedures outlined above, the compounds in Table11 were prepared:

TABLE 11

Example R A³ LCMS (M + 1)⁺ 269

546.1, 548.1, 550.1 270

548.1, 550.1, 552.1, 554.1 271

514.2, 516.2 272

516.2, 518.1, 520.2

Following the general procedures outlined above, the compounds in Table12 were prepared:

TABLE 12

Example R LCMS (M + 1)⁺ 273

518.2 274

572.2 275

492.1 276

506.2 277

495.0, 497.0 278

502.0, 504.0, 506.1 279

495.0, 497.0 280

489.0, 491.0

Example 281

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-2′-hydroxy-5′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]-methyl}-4-methyl-1,3-oxazolidin-2-oneStep A:4-fluoro-2′-(iodomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-ol

A solution of[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol(71.5 mg, 0.209 mmol) and iodine (610 mg, 2.40 mmol) inphenyltrimethylsilane (877 μL) was heated at 110° C. in a sealed tubeovernight. The reaction was cooled to room temperature, diluted with 1NHCl (10 mL) and extracted with EtOAc (3×20 mL). The combined extractswere washed with 10% Na₂S₂O₃ (20 mL), dried (Na₂SO₄) and concentrated invacuo to give the crude product. This was purified by flashchromatography (Si, 12×160 mm, 0-20% EtOAc in hexanes gradient) toafford4-fluoro-2′-(iodomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-ol.R_(f)=0.65 (20% EtOAc in hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.81 (s,1H), 7.60 (d, J=7.9 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.10 (d, J=8.3 Hz,1H), 6.69 (d, J=11.1 Hz, 1H), 4.82 (s, 1H), 4.41 (d, J=9.4 Hz, 1H), 4.23(d, J=9.3 Hz, 1H), 3.27-3.19 (m, 1H), 1.27 (br s, 6H).

Step B:2-{[4-fluoro-2′-(iodomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-yl]oxy}tetrahydro-2H-pyran

p-Toluenesulfonic acid (2.8 mg, 0.0145 mmol) was added to a solution of4-fluoro-2′-(iodomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-ol(63.4 mg, 0.145 mmol) and 3,4-dihydro-2H-pyran (60.8 mg, 66 μL, 0.723mmol) in dry CH₂Cl₂ (7.2 mL) at room temperature under N₂ and thereaction was stirred for 3 days. The reaction mixture was diluted withsaturated NaHCO₃ (20 mL) and extracted with CH₂Cl₂ (3×20 mL). Thecombined extracts were dried (Na₂SO₄) and concentrated in vacuo to givethe crude product. This was purified by flash chromatography (Si, 12×160mm, 0-20% EtOAc in hexanes gradient) to afford2-{[4-fluoro-2′-(iodomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-yl]oxy}tetrahydro-2H-pyran.R_(f)=0.74 (10% EtOAc in hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.75 (s,1H), 7.62 (d, J=8.3 Hz, 0.5H), 7.59 (d, J=8.3 Hz, 0.5H), 7.53 (t, J=7.3Hz, 0.5H), 7.41 (s, 0.5H), 7.32 (d, J=7.9 Hz, 0.5H), 7.25 (d, J=7.9 Hz,0.5H), 7.15 (t, J=9.4 Hz, 0.5H), 6.99 (d, J=12.2 Hz, 0.5H), 6.94 (d,J=12.2 Hz, 0.5H), 6.69 (d, J=11.0 Hz, 0.5H), 5.37 (s, 0.5H), 5.23 (s,0.5H), 5.13 (s, 1H), 4.45 (d, J=9.6 Hz, 0.5H), 4.40 (d, J=9.6 Hz, 0.5H),4.31 (d, J=9.6 Hz, 0.5H), 4.23 (d, J=9.6 Hz, 0.5H) 3.76 (m, 0.5H),3.66-3.54 (m, 1.5H), 3.29-3.21 (m, 1H), 1.68-1.44 (m, 4H) 1.32-1.26 (m,6H).

Step C:(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-2′-hydroxy-5′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]-methyl}-4-methyl-1,3-oxazolidin-2-one

Sodium hydride (60% dispersion in mineral oil, 1.9 mg, 0.0485 mmol) wasadded to a stirred solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-onein dry DMF (1 mL) and the reaction was stirred for 30 min, A solution of2-{[4-fluoro-2′-(iodomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-yl]oxy}tetrahydro-2H-pyran(16.9 mg, 0.324 mmol) in dry DMF (1 mL) was added by cannula and thereaction was stirred at room temperature overnight. The reaction wasdiluted with saturated NH₄Cl (10 mL) and water (5 mL) and extracted withEtOAc (3×20 mL). The combined extracts were dried (Na₂SO₄) andconcentrated in vacuo to give the crude product. A solution of the crudeproduct and p-toluenesulfonic acid (0.6 mg, 0.00324 mmol) in MeOH (5 mL)was stirred at room temperature overnight. The reaction mixture wasconcentrated in vacuo to give the crude product. This was purified byflash chromatography (Si, 12×160 mm, 0-35% EtOAc in hexanes gradient) toafford(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-2′-hydroxy-5′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.33 (20% EtOAc in hexanes). LCMS calc.=624.2; found=624.3 (M+1)⁺.¹H NMR (500 MHz, CDCl₃, 1:1 mixture of atropisomers) δ 7.86 (s, 1H),7.67 (m, 4H), 7.42 (d, J=7.1 Hz, 0.5H), 7.41 (d, J=7.1 Hz, 0.5H), 6.95(d, J=7.3 Hz, 0.5H), 6.94 (d, J=7.3 Hz, 0.5H), 6.70 (d, J=5.6 Hz, 0.5H),6.68 (d, J=5.6 Hz, 0.5H), 5.66 (d, J=8.0 Hz, 0.5H), 5.36 (d, J=8.1 Hz,0.5H), 4.93 (d, J=15.8 Hz, 0.5H), 4.88 (d, J=15.8 Hz, 0.5H), 4.18 (d,J=15.8 Hz, 0.5H), 4.00 (d, J=15.8 Hz, 0.5H), 3.87-3.83 (m, 0.5H),3.77-3.71 (m, 0.5H), 3.22-3.14 (m, 1H), 1.77 (br s, 1H), 1.27-1.17 (m,6H), 0.57 (d, J=6.5 Hz, 1.5H), 0.45 (d, J=6.5 Hz, 1.5H).

Following the general procedures outlined above, the compounds in Table13 were prepared:

TABLE 13 LCMS Example R (M + 1)⁺ 282

624.3

Example 283

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-3′-hydroxy-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-oneStep A:tert-butyl{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-methoxy}dimethylsilane

tert-Butyldimethylsilyl chloride (0.48 g, 3.21 mmol) and imidazole (0.50g, 7.30 mmol) were added successively to a stirred solution of[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol(1.00 g, 2.93 mmol) in dry CH₂Cl₂ (13.4 mL) at room temperature under N₂and the reaction was stirred overnight. Water (50 mL) was added and themixture was extracted with EtOAc (3×50 mL). The combined extracts weredried (MgSO₄) and concentrated in vacuo to give the crude product. Thiswas purified by flash chromatography (Si, 25×160 mm, 1% EtOAc inhexanes) to afford tert-butyl{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methoxy}dimethylsilaneas a colorless oil. R_(f)=0.16 (1% EtOAc in hexanes). LCMS calc.=457.2;found=457.2 (M+1)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.94 (s, 1H), 7.57 (d,J=7.8 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 6.69 (d,J=12.1 Hz, 1H), 4.63 (br s, 1H), 4.50 (br s, 1H), 3.75 (s, 3H),3.29-3.21 (m, 1H), 1.28 (d, J=6.9 Hz, 6H), 0.93 (s, 9H), 0.03 (s, 6H).

Step B:2′-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol

n-Butyllithium (1.6M in hexanes, 261 μL 0.417 mmol) was added dropwiseover 30-45 min with a syringe pump to a stirred solution oftert-butyl{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methoxy}dimethylsilane(200 mg, 0.438 mmol) in dry THF (0.5 mL) at −78° C. under N₂. Thereaction was stirred for a further 2 h at −78° C. after the addition togive a violet colored solution. Trimethyl borate (43.4 mg, 47 μL, 0.417mmol) was added dropwise and the reaction was stirred at −78° C. for 3h. The reaction mixture was warmed to 0° C. and acetic acid (25.1 mg, 24μL, 0.626 mmol) was added quickly followed by 30% aqueous hydrogenperoxide (52 μL, 0.459 mmol) dropwise. The reaction was stirred at roomtemperature overnight, diluted with water (10 mL) and extracted withEt₂O (3×20 mL). The combined extracts were washed with 50% saturatedFeSO₄ (20 mL), dried (Na₂SO₄) and concentrated in vacuo to give thecrude product. This was purified by flash chromatography (Si, 12×160 mm,0-100% EtOAc in hexanes gradient) to affordT-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol.R_(f)=0.32 (10% EtOAc in hexanes). LCMS calc.=473.1; found=473.2 (M+1)⁺.¹H NMR (600 MHz, CDCl₃) δ 7.95 (s, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.35 (d,J=7.9 Hz, 1H), 6.53 (d, J=7.8 Hz, 1H), 5.65 (s, 1H), 4.68 (br s, 1H),4.54 (br s, 1H), 3.42 (s, 3H), 3.26-3.20 (m, 1H), 1.25 (d, J=6.9 Hz,6H), 0.90 (s, 9H), 0.02 (s, 6H).

Step C:4-fluoro-2′-(hydroxymethyl)-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol

tert-Butylammonium fluoride (1M in THF, 179 μL, 0.179 mmol) was addeddropwise to a stirred solution of2′-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol(76.8 mg, 0.163 mmol) in THF (2 mL) at 0° C. and the reaction wasallowed to warm to room temperature overnight. Saturated NH₄Cl (10 ml)was added and the mixture was extracted with EtOAc (3×20 mL). Thecombined extracts were dried (Na₂SO₄) and concentrated in vacuo to givethe crude product. This was purified by flash chromatography (Si, 12×160mm, 0-40% EtOAc in hexanes gradient) to afford4-fluoro-2′-(hydroxymethyl)-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol.R_(f)=0.26 (20% EtOAc in hexanes). ¹H NMR (600 MHz, CDCl₃) δ 7.85 (s,1H), 7.63 (d, J=7.9 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 6.53 (d, J=7.7 Hz,1H), 4.50 (br s, 1H), 4.47 (s, 1H), 3.42 (s, 3H), 3.25-3.19 (m, 1H),1.24 (br s, 6H).

Step D:2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol

A solution of triphenylphosphine (102.8 mg, 0.392 mmol) in dry CH₂Cl₂ (2mL) was added by cannula to a stirred solution of carbon tetrabromide(130 mg, 0.392 mmol) and4-fluoro-2′-(hydroxymethyl)-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol(58.5 mg, 0.163 mmol) in dry CH₂Cl₂ (2 mL) at 0° C. under N₂ and thereaction was stirred at room temperature overnight. The reaction mixturewas concentrated in vacuo to give the crude product. This was purifiedby flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanes gradient)to afford2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol.R_(f)=0.55 (20% EtOAc in hexanes). ¹H NMR (600 MHz, CDCl₃) δ 7.84 (s,1H), 7.61 (d, J=7.9 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 6.69 (d, J=7.8 Hz,1H), 5.59 (s, 1H), 4.50 (d, J=9.6 Hz, 1H), 4.39 (d, J=9.7 Hz, 1H), 3.47(s, 3H), 3.29-3.23 (m, 1H), 1.27 (d, J=6.9 Hz, 6H).

Step E:2-{[2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]oxy}tetrahydro-2H-pyran

3,4-Dihydro-2H-pyran (51.9 mg, 56 μL, 0.617 mmol) was added to a stirredsolution of p-toluenesulfonic acid (2.3 mg, 0.0123 mmol) and2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol(52.0 mg, 0.123 mmol) in dry CH₂Cl₂ (6.1 mL) at room temperature underN₂ and the reaction was stirred overnight. The reaction mixture wasdiluted with CH₂Cl₂ (45 mL) and washed with saturated NaHCO₃ (5 mL) and30% saturated Na₂SO₃ (5 mL), dried (Na₂SO₄) and concentrated in vacuo togive the crude product. This was purified by flash chromatography (Si,12×160 mm, 0-40% EtOAc in hexanes gradient) to afford2-{[2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]oxy}tetrahydro-2H-pyran.R_(f)=0.59 (20% EtOAc in hexanes). ¹H NMR (600 MHz, CDCl₃) 7.82 (s, 1H),7.60 (d, J=7.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H),5.77 (s, 1H), 4.97 (dd, J=4.9, 2.9 Hz, 1H), 4.49 (d, J=9.8 Hz, 1H), 4.37(d, J=9.8 Hz, 1H), 3.89-3.87 (m, 1H), 3.61-3.49 (m, 1H), 3.46 (s, 3H),3.27-3.21 (m, 1H), 1.89-1.83 (m, 1H), 1.78-1.70 (m, 1H) 1.64-1.48 (m,3H), 1.26 (d, J=6.8 Hz, 6H).

Step F:(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-3′-hydroxy-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Sodium hydride (60% dispersion in mineral oil, 14.7 mg, 0.368 mmol) wasadded to a stirred solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(57.7 mg, 0.184 mmol) in dry THF (2 mL) at room temperature. After 30min a solution of2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol(62.0 mg, 0.123 mmol) in dry THF (2 mL) was added by cannula and thereaction mixture was stirred overnight. Saturated NH₄Cl (10 mL) wasadded and the mixture was extracted with EtOAc (3×20 mL). The combinedextracts were dried (Na₂SO₄) and concentrated in vacuo to give the crudeproduct. This was purified by flash chromatography (Si, 12×160 mm, 0-40%EtOAc in hexanes gradient) to afford(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-3′-hydroxy-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.25 (20% EtOAc in hexanes). LCMS calc.=654.2; found=654.2 (M+1)⁺.¹H NMR (500 MHz, CDCl₃, 1:1 mixture of atropisomers) δ 7.86 (m, 1H),7.73-7.63 (m, 4H) 7.44 (m, 1H), 6.55 (d, J=7.6 Hz, 0.5H), 6.52 (d, J=7.7Hz, 0.5H), 5.71 (br s, 1H), 5.60 (d, J=8.0 Hz, 0.5H), 5.54 (d, J=8.0 Hz,0.5H), 4.87 (d, J=16.0 Hz, 0.5H), 4.72 (d, J=16.1 Hz, 0.5H), 4.23 (d,J=16.1 Hz, 0.5H), 3.98 (d, J=15.9 Hz, 0.5H), 3.93-3.85 (m, 0.5H),3.77-3.71 (m, 0.5H), 3.51 (s, 1.5H), 3.47 (s, 1.5H), 3.25-3.17 (m, 1H),1.26-1.18 (m, 6H), 0.58 (d, J=6.5 Hz, 1.5H), 0.38 (d, J=6.6 Hz, 1.5H).

Example 284

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-2′,3′-dihydroxy-5′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Boron tribromide (17.4 mg, 6.6 μL, 0.0692 mmol) was added to a stirredsolution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-3′-hydroxy-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one(22.6 mg, 0.0346 mmol) in dry CH₂Cl₂ (1 mL) at −78° C. at roomtemperature under N₂ and the reaction was stirred for 8 h. The reactionwas diluted with water (5 mL) and extracted with EtOAc (3×20 mL). Thecombined extracts were dried (Na₂SO₄) and concentrated in vacuo to givethe crude product. This was purified by chiral HPLC (IA column, 20×250mm, 15% i-PrOH in heptane) to afford(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-2′,3′-dihydroxy-5′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.R_(f)=0.24 (20% EtOAc in hexanes). LCMS calc.=640.2; found=640.2 (M+1)⁺.¹H NMR (600 MHz, CDCl₃, 1:1 mixture of atropisomers) δ 7.85 (s, 1H),7.70-7.62 (m, 4H), 7.41 (m, 1H), 6.52 (s, 0.5H), 6.51 (s, 0.5H), 6.20(br s, 2H), 5.65 (d, J=7.9 Hz, 0.5H), 5.38 (d, J=8.0 Hz, 0.5H), 5.00 (d,J=15.5 Hz, 0.5H), 4.92 (d, J=15.6 Hz, 0.5H), 4.15 (d, J=15.5 Hz, 0.5H),4.02 (d, J=15.6 Hz, 0.5H), 3.88 (t, J=6.7 Hz, 0.5H), 3.77 (t, J=6.7 Hz,0.5H), 3.19-3.13 (m, 1H), 1.26-1.17 (m, 6H), 0.59 (d, J=6.1 Hz, 1.5H),0.48 (d, J=6.2 Hz, 1.5H).

Step A: 2-(2-fluoro-3,4-dimethoxyphenyl)propan-2-ol

A solution of methylmagnesium chloride (3M in THF, 1.74 mL, 5.22 mmol)was added dropwise to a stirred solution of1-(2-fluoro-3,4-dimethoxyphenyl)ethanone (J. Chem. Soc. Perkin Trans. 21994, 547-555) (646 mg, 3.26 mmol) in heptane (3.1 mL) and THF (1.4 mL)at −20° C. under N₂. The reaction was allowed to warm to roomtemperature and was stirred for 4 h. 50% Saturated NH₄Cl (20 mL) wasadded and the mixture was extracted with EtOAc (3×20 mL). The combinedextracts were dried (Na₂SO₄) and concentrated in vacuo to give2-(2-fluoro-3,4-dimethoxyphenyl)propan-2-ol as a colorless oil. LCMScalc.=197.1; found=197.1 (M−OH)⁺. ¹H NMR (600 MHz, CDCl₃) δ 7.14 (t,J=8.8 Hz, 1H), 6.61 (dd, J=8.8, 1.4 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H),2.56-2.25 (br s, 1H), 1.58 (s, 6H).

Step B: 2-fluoro-1-isopropyl-3,4-dimethoxybenzene

A suspension of 10% palladium on carbon (69.8 mg) in a solution of2-(2-fluoro-3,4-dimethoxyphenyl)propan-2-ol (698 mg, 3.26 mmol) in 5NHCl (0.7 mL) and EtOH (5.6 mL) was stirred at room temperature under H₂(15 psi) overnight. The mixture was filtered through a plug of Celiteand washed with EtOAc (˜75 mL). The filtrate was washed with 50%saturated brine (10 mL), dried (MgSO₄) and concentrated in vacuo toafford 2-fluoro-1-isopropyl-3,4-dimethoxybenzene. ¹H NMR (500 MHz,CDCl₃) δ 6.86 (t, J=8.3 Hz, 1H), 6.63 (dd, J=8.7, 1.5 Hz, 1H), 3.89 (s,3H), 3.84 (s, 3H), 3.19-3.11 (m, 1H), 1.22 (d, J=6.8 Hz, 6H).

Step C: 1-bromo-3-fluoro-2-isopropyl-4,5-dimethoxybenzene

Bromine (80.6 mg, 26 μL, 0.504 mmol) was added to a solution of2-fluoro-1-isopropyl-3,4-dimethoxybenzene (50.0 mg, 0.252 mmol) andpotassium acetate (49.5 mg, 0.504 mmol) in acetic acid (1 mL) at roomtemperature and the reaction was stirred overnight. The reaction wasdiluted with water (10 mL) and saturated Na₂SO₃ (10 mL), then extractedwith EtOAc (3×20 mL). The combined extracts were washed with saturatedNaHCO₃ (2×10 mL), dried (MgSO₄) and concentrated in vacuo to afford1-bromo-3-fluoro-2-isopropyl-4,5-dimethoxybenzene. ¹H NMR (600 MHz,CDCl₃) δ 6.86 (d, J=2.0 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.43-3.34(m, 1H), 1.31-1.29 (dd, J=7.1, 1.4 Hz, 6H).

Following the general procedures outlined above, the compounds in Table14 were prepared:

TABLE 14

LCMS Example A³ (M + 1)⁺ 285

668.1 286

668.1 287

640.1 288

640.1

Example 289

5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-(difluoromethyl)-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-oneStep A:2′-({5-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methoxy-4′-(trifluoromethyl)biphenyl-3-carbaldehyde

A mixture of5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one(Example 66, 50 mg; 0.0858 mmol), 5-formyl-2-methoxyphenyl boronic acid(46 mg; 0.257 mmol), tetrakis(triphenylphosphine)palladium (0) (12 mg;0.0103 mmol), and sodium carbonate (74 mg) in benzene/ethanol/water(2.8/0.4/1.2 mL) was heated at reflux for 60 h. The reaction was dilutedwith EtOAc (30 mL) and washed successively with H₂O (10 mL) and brine(10 mL), dried over MgSO₄, filtered, and concentrated in vacuo. Thecrude product was purified by flash silica gel chromatography (0-50%EtOAc/hexanes gradient) to afford2′-({5-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methoxy-4′-(trifluoromethyl)biphenyl-3-carbaldehydeas a yellow oil. LCMS=592.1 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz, mixture ofatropisomers): δ 9.98 (s, 1H), 7.99-7.96 (m, 1H), 7.90 (s, 1H), 7.75 (s,2H), 7.69-7.64 (m, 2 Hz), 7.53 (s, 1H), 7.41-7.38 (m, 1H), 7.17-7.14 (m,1H), 5.37 (t, J=8.2 Hz, 1H), 4.59 (d, J=15.3 Hz, 1H), 4.37 (d, J=15.6Hz, 1H), 3.92 (s, 3H), 3.67-3.64 (m, 1 Hz), 3.19-3.16 (m, 1H).

Step B:5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-(difluoromethyl)-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one

Diethylaminosulfur trifluoride (22 μL, 0.1675 mmol) was added dropwiseto a stirred solution of2′-({5-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methoxy-4′-(trifluoromethyl)biphenyl-3-carbaldehyde(Step A, 50 mg, 0.0838 mmol) in CH₂Cl₂ (1 mL) at 0° C. The reactionstirred at room temperature for 14 h. The reaction was quenched with H₂Oat 0° C., diluted with CH₂Cl₂ (10 mL), washed with H₂O (10 mL) and brine(10 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude product was purified by flash silica gel chromatography (0-25%EtOAc/hexanes gradient) to afford5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-(difluoromethyl)-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-oneas a clear glass. LCMS=594.2 (M−19)⁺. ¹H NMR (benzene-d₆, 500 MHz,mixture of atropisomers): δ 7.64 (s, 1H), 7.38-7.36 (m, 2H), 7.30-7.26(m, 2H), 7.14-7.11 (m, 2H), 6.85 (d, J=8 Hz, 1H), 6.45 (d, J=8.5 Hz,1H), 6.37-6.13 (m, 1H), 4.46-4.38 (m, 2H), 3.79-3.76 (m, 1H), 3.21 (s,3H), 2.36 (t, J=8.7 Hz, 1H), 2.05 (t, J=8.4 Hz, 1H).

This compound was separated into its enantiomers(5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-(difluoromethyl)-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-oneand(5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-(difluoromethyl)-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-oneusing chiral HPLC (15% IPA/heptane, AS column).

Example 290

5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-4,5′-bis(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-oneStep A: 2-iodo-1-methoxy-4-(trifluoromethyl)benzene

To a stirred solution of 2-methoxy-5-(trifluoromethyl)aniline (500 mg,2.62 mmol) in CH₂Cl₂ (10 mL) was added t-butyl nitrite (467 μL, 3.93mmol). The reaction was stirred for 5 min prior to addition of iodine(1.3 g, 5.24 mmol), and then heated at 70° C. for 2 h. The reaction wascooled, diluted with CH₂Cl₂ (10 mL), washed with sat. Na₂S₂O₃ (10 mL)and brine (10 mL), dried over Na₂SO₄, filtered and concentrated invacuo. The crude product was purified by flash silica gel chromatography(hexanes) to afford 2-iodo-1-methoxy-4-(trifluoromethyl)benzene as alight yellow solid. ¹H NMR (CDCl₃, 500 MHz): δ 8.05 (d, J=2 Hz, 1H),7.61 (dd, J=8.7, 1.8 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 3.97 (s, 3H).

Step B: [2-methoxy-5-(trifluoromethyl)phenyl]boronic acid

n-Butyl lithium (1.6M in hexanes, 456 μL, 0.729 mmol) was added dropwiseto a stirred solution of 2-iodo-1-methoxy-4-(trifluoromethyl)benzene(Step A, 200 mg, 0.662 mmol) in THF (1.5 mL) at −78° C. under anatmosphere of nitrogen. The reaction stirred at −78° C. for 30 min priorto the addition of triisopropyl borate (458 μL, 1.986 mmol). Thereaction stirred an additional 2 h at −78° C. and was quenched with sat.NH₄Cl. The mixture was extracted with CH₂Cl₂ and the organic phase waswashed with NaHCO₃ (15 mL) and brine (15 mL), dried (Na₂SO₄), filtered,conc. in vacuo to afford [2-methoxy-5-(trifluoromethyl)phenyl]boronicacid which was carried on without purification.

Step C:5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-4,5′-bis(trifluoromethyl)-biphenyl-2-yl]-methyl}-1,3-oxazolidin-2-one

5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one(Example 66, 100 mg; 0.171 mmol) was treated with[2-methoxy-5-(trifluoromethyl)phenyl]boronic acid (Step B, 113 mg; 0.514mmol), tetrakis(triphenylphosphine)palladium (0) (24 mg; 0.0206 mmol),and sodium carbonate (148 mg) as described in Example 291 to afford5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-4,5′-bis(trifluoromethyl)-biphenyl-2-yl]methyl}-1,3-oxazolidin-2-oneas a clear glass. LCMS=612.1 (M−19)⁺. ¹H NMR (benzene-d₆, 500 MHz,mixture of atropisomers): δ 7.61 (s, 1H), 7.40-7.36 (m, 1H), 7.31 (s,1H), 7.27-7.23 (m, 4H), 6.74-6.72 (m, 1H), 6.35 (d, J=8.7 Hz, 1H),4.42-4.32 (m, 2H), 3.70 (d, J=15.8 Hz, 1H), 3.14 (s, 3H), 2.28 (t, J=8.7Hz, 1H), 1.98 (t, J=8.2 Hz, 1H).

This compound was separated into its enantiomers(5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-4,5′-bis(trifluoromethyl)-biphenyl-2-yl]methyl}-1,3-oxazolidin-2-oneand(5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-4,5′-bis(trifluoromethyl)-biphenyl-2-yl]methyl}-1,3-oxazolidin-2-oneusing chiral HPLC (5% EtOH/heptane, AS column).

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(400 mg, 1.28 mmol) was treated with NaH (60% in oil, 128 mg, 3.2 mmol)and 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (Example 70, 466mg, 1.28 mmol) as described in Example 66 to afford(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-oneas a white solid. LCMS=598.0 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz): δ 8.06 (d,J=8.2 Hz, 1H), 7.93 (s, 1H), 7.82 (s, 2H), 7.61 (s, 1H), 7.33 (dd,J=8.2, 1.4 Hz, 1H), 5.79 (d, J=7.8 Hz, 1H), 4.91 (d, J=16 Hz, 1H), 4.40(d, J=16 Hz, 1H), 4.16-4.06 (m, 1H), 0.83 (d, J=6.4 Hz, 3H).

Example 291

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-methoxy-5-methyl-3-thienyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-oneStep A: 3,5-dibromo-2-methoxythiophene

To a stirred solution of 2-methoxythiophene (1 g, 8.76 mmol) in CH₂Cl₂(18 mL) at 0° C. was added N-bromosuccinimide (3.12 g, 17.52 mmol)slowly. The reaction was allowed to warm to room temperature and stirredfor 14 h. The reaction was cooled in an ice bath and filtered. Thefiltrate was washed with sat. NaHCO₃ (2×25 mL). The aqueous layer wasneutralized with 1N HCl and extracted with CHCl₃ (3×25 mL). The combinedorganic layers were washed with brine (25 mL), dried (Na₂SO₄), filteredand concentrated in vacuo. The crude product was purified by flashsilica gel chromatography (hexanes) to afford3,5-dibromo-2-methoxythiophene as a pale pink oil. LCMS=272.9 (M+)⁺.

Step B: 3-bromo-2-methoxy-5-methylthiophene

n-Butyl lithium (2.0M in pentane, 0.97 mL, 1.93 mmol) was added to astirred solution of 3,5-dibromo-2-methoxythiophene (Step A, 500 mg, 1.84mmol) in THF (5 mL) at −78° C. under an atmosphere of N₂. The reactionstirred at −78° C. for 1 h prior to addition of methyl iodide (114 μL,1.84 mmol). The reaction was allowed to warm to room temperature andstirred for 20 h. The solvent was removed under reduced pressure and theresidue was partitioned between EtOAc (15 mL0 and H₂O (15 mL). Theaqueous layer was re-extracted with ether (2×15 mL) and the combinedorganic layers were washed with H₂O (15 mL) and brine (15 mL), dried(MgSO₄), filtered and concentrated in vacuo. The crude product waspurified by flash silica gel chromatography (hexanes) to afford3-bromo-2-methoxy-5-methylthiophene as a yellow oil. ¹H NMR (CDCl₃, 500MHz): δ 6.44 (s, 1H), 3.95 (s, 3H), 2.41 (s, 3H).

Step C: (2-methoxy-5-methyl-3-thienyl)boronic acid

A stirred mixture of 3-bromo-2-methoxy-5-methylthiophene (Step B, 296mg, 1.43 mmol) and triisopropyl borate (396 μL, 2.15 mmol) intoluene/THF (2.3/0.6 mL) was cooled to −70° C. under an atmosphere ofN₂. n-Butyl lithium (2.0M in pentane, 1.07 mL, 2.15 mmol) was addeddropwise via a syringe pump over 1 h. The reaction stirred at −70° C.for 40 min more and was quenched with 2N HCl (2 mL) at −20° C. Thereaction was partitioned between EtOAc (15 mL) and H₂O (15 mL). Theaqueous layer was extracted with EtOAc (10 mL); the combined organiclayers were washed with brine (15 mL), dried (Na₂SO₄), filtered, andconcentrated in vacuo to afford (2-methoxy-5-methyl-3-thienyl)boronicacid as a yellow oil. This material was used without furtherpurification.

Step D:(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-methoxy-5-methyl-3-thienyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one(Intermediate 21, 13 mg; 0.0219 mmol) was treated with(2-methoxy-5-methyl-3-thienyl)boronic acid (Step C, 10.4 mg; 0.0657mmol), tetrakis(triphenylphosphine)palladium (0) (3 mg; 0.0026 mmol),and sodium carbonate (20 mg) as described in Example 291 to afford(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-methoxy-5-methyl-3-thienyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-oneas a yellow glass. LCMS=598.2 (M+1)⁺. ¹H NMR (benzene-d₆, 500 MHz): δ7.75 (s, 1H), 7.57 (s, 1H), 7.31-29 (m, 1H), 7.24 (s, 2H), 7.12-7.10 (m,1H), 6.14 (s, 1H), 4.96 (d, J=16 Hz, 1H), 4.57 (d, J=8 Hz, 1H), 3.99 (d,J=15.8 Hz, 1H), 3.30 (s, 3H), 2.95-2.92 (m, 1H), 2.05 (s, 3H), −0.28 (d,J=6.7 Hz, 3H).

Following the general procedures outlined above, the compounds in Table15 were prepared:

TABLE 15

Compound A³ LCMS 292

608.1 (M − 19)⁺ 293

610.1 (M + 1)⁺ 294

614.2 (M + 1)⁺ 295

682.1 (M + 42)⁺ 296

622.2 (M + 1)⁺ 297

584.2 (M + 1)⁺

Example 298

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-2′-methoxy-5′-(2-methyl-1,3-dioxolan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-1,3-oxazolidin-2-one

A mixture of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one(Intermediate 21, 7.34 g, 12.29 mol),[4-fluoro-2-methoxy-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]boronic acid(5.5 g, 21.48 mol), tetrakis(triphenylphosphine)palladium (0) (1.7 g;1.47 mol), and sodium carbonate (10 g) in benzene/EtOH,/H₂O (203/29/86mL) was heated at reflux for 14 h. The reaction was quenched with H₂Oand partitioned between EtOAc (250 mL) and H₂O (75 mL). The aqueouslayer was re-extracted with EtOAc (3×200 mL). The combined extracts werewashed with brine (100 mL), dried (MgSO₄), filtered, and concentrated invacuo. The crude product was purified by flash silica gel chromatography(0-25% EtOAc/hexanes gradient) to afford(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-2′-methoxy-5′-(2-methyl-1,3-dioxolan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-1,3-oxazolidin-2-oneas an amorphous solid. LCMS=682.2 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz,mixture of atropisomers): δ 7.86 (s, 1H), 7.71 (S, 3H), 7.65-7.61 (m,1H), 7.37-7.34 (m, 1H), 7.32-7.28 (m, 1H), 6.75 (dd, J=12.4, 3.6 Hz,1H), 5.58 (d, J=8.1 Hz, 1H), 4.89 (d, J=15.8 Hz, 1H), 4.08-4.04 (m, 2H),3.91-3.76 (m, 7H), 1.73 (d, J=10.5 Hz, 3H), 0.4 (d, J=6.5 Hz, 3H).

Example 299

(4S,5R)-3-{[5′-acetyl-4′-fluoro-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

To a stirred solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-2′-methoxy-5′-(2-methyl-1,3-dioxolan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-1,3-oxazolidin-2-one(8 g, 0.0118 mol) in acetone (400 mL) was added p-toluenesulfonic acidmonohydrate (670 mg, 0.0035 mol). The reaction stirred at roomtemperature for 14 h. The reaction was partitioned between EtOAc (250mL) and sat. NaHCO₃ (250 mL). The aqueous layer was re-extracted withEtOAc (3×250 mL) and the combined organic layers were washed with brine(200 mL), dried (MgSO₄), filtered, and concentrated in vacuo. The crudeproduct was purified by flash silica gel chromatography (0-25%EtOAc/hexanes gradient) to afford(4S,5R)-3-{[5′-acetyl-4′-fluoro-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-oneas a yellow solid. LCMS=638.2 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz, mixture ofatropisomers): δ 7.87 (s, 1H), 7.81-7.79 (m, 1H), 7.74 (s, 1H), 7.70 (s,2H), 7.59 (s, 1H), 7.39 (d, J=8 Hz, 1H), 6.80 (d, J=12.8 Hz, 1H), 5.27(d, J=8.2 Hz, 1H), 4.97 (d, J=15.3 Hz, 1H), 4.04 (d, J=15.5 Hz, 1H),3.94 (s, 3H), 3.72-3.66 (m, 1H), 2.67-2.64 (m, 3H), 0.62 (d, J=6.4 Hz,3H).

Example 300

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropenyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Methyl magnesium iodide (29 μL, 0.085 mmol) was added dropwise to asolution of(4S,5R)-3-{[5′-acetyl-4′-fluoro-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(30 mg, 0.047 mmol) in diethyl ether (2 mL) at room temperature. Thereaction was carefully heated at reflux 4 h. Additional methyl magnesiumiodide (63 μL, 0.19 mmol) and ether (1 mL) was added and the reactionwas refluxed for 3 h. The reaction was quenched with sat. NH₄Cl andextracted with EtOAc (3×25 mL). The combined extracts were washed withbrine (25 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude product was purified by flash silica gel chromatography (0-25%EtOAc/hexanes gradient) to afford(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropenyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-oneas a clear glass. LCMS=636.3 (M+1)⁺. ¹H NMR (benzene-d₆, 500 MHz,mixture of atropisomers): δ 7.59 (s, 1H), 7.55 (s, 1H), 7.35 (d, J=8 Hz,1H), 7.30-7.27 (m, 2H), 6.99-6.96 (m, 2H), 6.45 (d, J=12.9 Hz, 1H), 5.32(d, J=16.9 Hz, 1H), 5.16-5.15 (m, 1H), 4.90 (d, J=16.3 Hz, 1H), 4.48 (d,J=7.7 Hz, 1H), 3.70 (d, J=6.4 Hz, 1H), 3.16 (s, 3H), 2.85-2.79 (m, 1H),2.12 (s, 3H), −0.025 (d, J=6.5 Hz, 3H).

Example 301

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-2′-hydroxy-5′-isopropenyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

To a stirred solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropenyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one(Example 300, 50 mg, 0.078 mmol) in DMF (450 μL) was added lithiumchloride (13.4 mg, 0.315 mmol). The vial was sealed and the reaction washeated at 160° C. for 14 h. 10% NaOH (10 mL) was added and the resultantsolution was extracted with ether (3×10 mL). The aqueous layer wasacidified to pH˜3 with 3N HCl and was re-extracted with ether (3×25 mL).The combined organic extracts were washed with brine (25 mL), dried(MgSO₄), filtered, and concentrated in vacuo. The crude product waspurified by flash silica gel chromatography (0-25% EtOAc/hexanesgradient) to afford(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-2′-hydroxy-5′-isopropenyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-oneas a clear glass. LCMS=622.1 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz, mixture ofatropisomers): δ 7.90 (s, 1H), 7.76-7.70 (m, 4H), 7.48-7.45 (m, 1H),7.11-7.07 (m, 1H), 6.75 (d, J=11.7 Hz, 1H), 5.71 (d, J=7.8 Hz, 1H),5.59-5.56 (m, 1H), 5.25-5.21 (m, 2H), 4.81 (d, J=15.4 Hz, 1H), 4.04 (d,J=15.6 Hz, 1H), 3.97-3.92 (m, 1H), 2.13 (s, 3H), 0.58 (d, J=6.6 Hz, 3H).

Example 302

(4S)-4-benzyl-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-methyl}-1,3-oxazolidin-2-one

A stirred suspension of sodium hydride (60% in oil, 37 mg, 0.926 mmol)in THF (1 mL) was treated at 0° C. with (S)-4-benzyl-2-oxazolidinone (33mg, 0.185 mmol) dissolved in THF (1 mL), under an atmosphere of N₂. Thereaction was stirred for 20 min and a solution of2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl(Intermediate 10, 50 mg, 0.124 mmol) in THF (1 mL) was added dropwise.The reaction was stirred at room temperature for 60 h. The reaction wasquenched with H₂O (1 mL) and partitioned between EtOAc (25 mL) and H₂O(10 mL). The aqueous phase was re-extracted with EtOAc (3×15 mL) and thecombined organic extracts were washed with brine (25 mL), dried (MgSO₄)and concentrated in vacuo to give the crude product. This was purifiedby flash silica-gel chromatography (0-25% EtOAc/hexanes gradient) toafford(4S)-4-benzyl-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-oneas a clear glass. LCMS=502.3 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz, mixture ofatropisomers) δ 7.69-7.64 (m, 1H), 7.58 (s, 1H), 7.39-7.36 (m, 1H),7.29-7.24 (m, 3H), 7.06 (d, J=8.5 Hz, 1H), 6.97-6.91 (m, 2H), 6.73 (d,J=11.7, 1H), 4.79 (d, J=15.8 Hz, 1H), 4.30 (d, J=15.8 Hz, 1H), 4.08-4.05(m, 1H), 3.99-3.97 (m, 1H), 3.76 (s, 3H), 3.65-3.58 (m, 1H), 3.27-3.17(m, 1H), 2.81 (dd, J=13.5, 4.1 Hz, 1H), 2.45-2.40 (m, 1H), 1.30-1.4 (m,6H).

Example 303

(4S)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-(4-methylbenzyl)-1,3-oxazolidin-2-oneStep A: (2S)-2-amino-3-(4-methylphenyl)propan-1-ol

A mixture of lithium aluminum hydride (254 mg, 6.696 mmol) in THF (20mL) was heated at reflux for 1 h, then cooled in an ice bath.(S)-4-Methylphenylalanine (500 mg, 2.79 mmol) was added portionwise andthe resultant mixture was heated at reflux for 14 h. The excess lithiumaluminum hydride was decomposed by successive addition of H₂O (1 mL),10% aq. NaOH (10 mL) and H₂O (2.5 mL). The mixture was filtered and thesolid was washed with THF. The filtrate was concentrated in vacuo andthe residue was dissolved in CHCl₃ (50 mL), washed with 5% aq. NaOH (25mL), H₂O (25 mL) and brine (25 mL), dried (MgSO₄), filtered, andconcentrated in vacuo to afford(2S)-2-amino-3-(4-methylphenyl)propan-1-ol as an off-white solid. ¹H NMR(CD₃OD, 500 MHz) δ 7.13-7.09 (m, 4H), 3.52 (dd, J=10.7, 4.6 Hz, 1H),3.36 (dd, J=10.7, 6.9 Hz, 1H), 3.04-2.99 (m, 1H), 2.73 (dd, J=13.5, 6.2Hz, 1H), 2.53 (dd, J=13.5, 7.7 Hz, 1H), 2.30 (s, 3H).

Step B: (4S)-4-(4-methylbenzyl)-1,3-oxazolidin-2-one

A stirred solution of (2S)-2-amino-3-(4-methylphenyl)propan-1-ol (StepA, 460 mg, 2.79 mmol) in CH₂Cl₂ (20 mL) at 0° C. was treated withdiisopropylethylamine (2.92 mL, 16.74 mmol) and triphosgene (414 mg,1.39 mmol) under an atmosphere of N₂. The reaction stirred at 0° C. for3 h. The reaction was quenched with sat. NaHCO₃ (10 mL) and extractedwith EtOAc (4×20 mL). The combined organic layers were washed with brine(25 mL), dried (MgSO₄), filtered and concentrated in vacuo. The crudeproduct was purified by flash silica gel chromatography (0-70%EtOAc/hexanes gradient) to afford(4S)-4-(4-methylbenzyl)-1,3-oxazolidin-2-one as a white solid.LCMS=192.2 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.17 (d, J=8 Hz, 2H), 7.09(d, J=7.7 Hz, 2H), 5.39 (br s, 1H), 4.48 (t, J=8.4 Hz, 1H), 4.37 (dd,J=8.6, 5.6 Hz, 1H), 4.11-4.06 (m, 1H), 2.86 (d, J=7.1 Hz, 2H), 2.36 (s,3H).

Step C:(4S)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-(4-methylbenzyl)-1,3-oxazolidin-2-one

(4S)-4-(4-methylbenzyl)-1,3-oxazolidin-2-one (Step B, 14 mg, 0.074 mmol)was treated with sodium hydride (60% in oil, 6.2 mg, 0.154 mmol) and2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl(Intermediate 10, 25 mg, 0.062 mmol) as described in Example 305 toafford(4S)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-(4-methylbenzyl)-1,3-oxazolidin-2-oneas clear gum. LCMS=516.4 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz, mixture ofatropisomers) δ 7.65-7.60 (m, 1H), 7.53 (s, 1H), 7.35-7.32 (m, 1H),7.06-7.20 (m, 2H), 6.82-6.75 (m, 2H), 6.69 (d, J=11.7 Hz, 1H), 4.67 (d,J=15.8 Hz, 1H), 4.06 (d, J=15.8 Hz, 1H), 4.04-4.00 (m, 1H), 3.96-3.93(m, 1H), 3.73 (s, 3H), 3.55-3.48 (m, 1H), 3.23-3.15 (m, 1H), 2.63 (dd,J=13.5, 3.6 Hz, 1H), 2.35 (d, J=13.5 Hz, 1H), 2.29 (s, 3H), 1.25-1.13(m, 6H).

Following the general procedures outlined above, the compounds in Table16 were prepared:

TABLE 16

LCMS Compound A² (M + 1)⁺ 304

516.4 305

516.4 306

532.3 307

532.3 308

520.4 309

520.3 310

536.3 311

536.3 312

536.3 313

516.4 314

516.4 315

516.4 316

516.4

Example 317

(4S,5S)-4-benzyl-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-1,3-oxazolidin-2-oneStep A: tert-butyl[1(S)-1-benzyl-2-oxopropyl]carbamate

A stirred solution ofN-(tert-butoxycarbonyl)-N-methoxy-N-methyl-L-phenylalaninamide (500 mg,1.62 mmol) in THF (3 mL) at −15° C. was treated with methyl magnesiumbromide (540 μL, 1.62 mmol) under an atmosphere of N₂. The reactionstirred at −15° C. for 15 min prior to dropwise addition of methylmagnesium bromide (1.08 mL, 3.24 mmol). The reaction stirred for 14 h atroom temperature and was quenched with 1N HCl (5 mL). The mixture waspartitioned between H₂O (15 mL) and EtOAc (20 mL) and the aqueous layerwas re-extracted with EtOAc (2×20 mL). The combined organic layers werewashed with H₂O (20 mL) and brine (20 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was purified by flash silicagel chromatography to affordtert-butyl[1(S)-1-benzyl-2-oxopropyl]carbamate as a white solid.LCMS=164.2 (M−BOC)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.34-7.26 (m, 3H), 7.18(d, J=7.1 Hz, 2H), 5.15 (br s, 1H), 4.59-4.56 (m, 1H), 3.14-2.99 (m,2H), 2.16 (s, 3H), 1.44 (s, 9H).

Step B: tert-butyl[1(S)-1-benzyl-2-hydroxypropyl]carbamate

A stirred solution of tert-butyl[1(S)-1-benzyl-2-oxopropyl]carbamate(Step A, 150 mg, 0.57 mmol) in dry MeOH (5 mL) at −20° C. was treatedwith sodium borohydride (44.2 mg, 1.169 mmol). The reaction stirred at−20° C. for 1 h and was quenched with H₂O (1 mL) and concentrated invacuo. The residue was dissolved in EtOAc (25 mL) and washedsequentially with H₂O (15 mL) and brine (15 mL), dried (Na₂SO₄),filtered and concentrated in vacuo. The crude product was purified bypreparatory thin-layer chromatography, eluting with 15% acetone/hexanesto afford tert-butyl[(1S,2R)-1-benzyl-2-hydroxypropyl]carbamate (45 mg)and tert-butyl[(1S,2S)-1-benzyl-2-hydroxypropyl]carbamate as whitesolids. tert-butyl[(1S,2R)-1-benzyl-2-hydroxypropyl]carbamate:LCMS=166.2 (M−BOC)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.34-7.31 (m, 2H),7.26-7.23 (m, 3H), 4.81 (br s, 1H), 3.83 (dq, J=6.4, 2.7 Hz, 1H),3.71-3.69 (m, 1H), 2.90 (d, J=7.3 Hz, 2H), 1.43 (s, 9H), 1.22 (d, J=6.5Hz, 3H). tert-butyl[(1S,2S)-1-benzyl-2-hydroxypropyl]carbamate:LCMS=166.2 (M−BOC)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.34-7.31 (m, 2H),7.26-7.23 (m, 3H), 4.58 (br s, 1H), 3.3.93-3.85 (m, 2H), 2.90 (dd,J=14.2, 5 Hz, 1H), 2.82-2.73 (m, 1H), 1.40 (s, 9H), 1.25 (d, J=6.4 Hz,3H).

Step C:(4S,5S)-4-benzyl-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-1,3-oxazolidin-2-one

tert-butyl[(1S,2R)-1-benzyl-2-hydroxypropyl]carbamate (Step B, 39 mg,0.148 mmol) was treated with sodium hydride (60% in oil, 12 mg, 0.309mmol) and2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl(Intermediate 10, 50 mg, 0.123 mmol) as described in Example 305 toafford(4S,5S)-4-benzyl-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-1,3-oxazolidin-2-oneas a clear glass. LCMS=516.4 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz, mixture ofatropisomers) δ 7.68 (d, J=11.5 Hz, 1H), 7.66-7.63 (m, 1H), 7.39-7.36(m, 1H), 7.28-7.23 (m, 3H), 7.07 (d, J=8.5 Hz, 1H), 6.94 (d, J=6.9 Hz,2H), 6.73 (d, J=4.8 Hz, 1H), 4.81 (d, J=16 Hz, 1H) 4.38 (d, J=16.1 Hz,1H), 4.28-4.23 (m, 1H), 3.78 (s, 3H), 3.29-3.17 (m, 2H), 2.81 (dd,J=13.3, 3.9 Hz, 1H), 2.38-2.28 (m, 1H), 1.29-1.13 (m, 6H), 0.98 (d,J=6.2 Hz, 3H).

Example 318

(4S,5R)-4-benzyl-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-1,3-oxazolidin-2-one

tert-butyl[(1S,2S)-1-benzyl-2-hydroxypropyl]carbamate (Example 317, StepB, 39 mg, 0.148 mmol) was treated with sodium hydride (60% in oil, 12mg, 0.309 mmol) and2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl(Intermediate 10, 50 mg, 0.123 mmol) as described in Example 305 toafford(4S,5R)-4-benzyl-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-1,3-oxazolidin-2-oneas a clear glass. LCMS=516.4 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz, mixture ofatropisomers) δ 7.64-759 (m, 2H), 7.33-7.30 (m, 1H), 7.28-7.21 (m, 2H),7.16 (s, 1H), 7.00-6.91 (m, 3H), 6.67 (d, J=3 Hz, 1H), 4.70 (d, J=2.7Hz, 1H), 4.52-4.47 (m, 1H), 3.95 (d, J=15.8 Hz, 1H), 3.70 (s, 3H),3.68-3.62 (m, 1H), 3.24-3.18 (m, 1H), 2.72-2.53 (m, 2H), 1.28-1.21 (m,6H), 1.19 (d, J=6.8 Hz, 3H).

Example 319

(4R)-4-benzyl-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-methyl}-1,3-oxazolidin-2-one

The title compound was prepared according to the procedure described inExample 67 starting from (R)-4-benzyl-2-oxazolidinone (49 mg, 0.27 mmol)and 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (100 mg, 0.27mmol) to afford the title compound as a colorless oil. R_(f)=0.35 (15%EtOAc/hexanes). LCMS 484 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) (atropisomerspresent) δ 7.72 (br s 1H), 7.65 (br s, 1H), 7.42 (m, 1H), 7.32-7.22 (m,3H), 7.08 (m, 1H), 6.90-6.84 (m, 3H), 4.81 (d, J=15.8 Hz, 1H), 4.35 (d,J=15.8 Hz), 4.28 (t, J=8.7 Hz, 1H), 3.96-3.92 (m, 3H), 3.78 (s, 3H),3.62-3.52 (m, 1H), 2.94-2.86 (m, 1H), 2.82 (dd, J=9.4, 3.9 Hz, 1H), 2.42(dd, J=9.6, 3.9 Hz), 1.26 (s, 3H), 1.10 (s, 3H).

Example 320

Example 322 was prepared according to the procedure described in Example14 starting from (S)-4-benzyl-5,5-dimethyl-2-oxazolidinone (10 mg, 0.05mmol) and2-(bromomethyl)-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl (20mg, 0.05 mmol) to afford the title compound as a colorless oil. LCMS 512(M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) (atropisomers present) δ 7.72 (br s 1H),7.31 (br s, 1H), 7.12-7.02 (m, 2H), 6.85-6.82 (m, 3H), 6.45-6.35 (m,4H), 4.61 (d, J=15.8 Hz, 1H), 4.21 (d, J=15.8 Hz), 3.21 (s, 2H), 3.16(s, 3H), 2.62-2.52 (m, 1H), 2.42-218 (m, 1H), 1.98 (m, 2H), 1.22 (d,J=7.1 Hz), 1.05 (d, J=7.1 Hz), 0.98 (s, 3H), 0.88 (s, 3H).

Example 321

(4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[4′-fluoro-5′-isopropyl]-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-pyrrolidin-2-oneStep A: ethyl 3-[3,5-bis(trifluoromethyl)phenyl]acrylate

To a suspension of NaH (60% suspension in oil, 168 mg, 4.96 mmol) in THF(3 mL) was added a solution of triethyl phosphonoacetate (0.5 mL, 2.52mmol) at 0° C., under an atmosphere of nitrogen. The reaction wasallowed to stir for 30 min at 0° C. and3,5-bis(trifluoromethyl)benzaldehyde (609 mg, 2.52 mmol) was added. Thereaction was allowed to warm to ambient temperature, stirred for anadditional 2 h and then concentrated in vacuo. The residue was dilutedwith EtOAc (20 mL), washed with H₂O, brine, dried over MgSO₄,concentrated and purified by flash chromatography with 10% EtOAc/hexanesto afford the title compound as a white solid. LCMS 313 (M+1)⁺.

Step B. methyl 3-[3,5-bis(trifluoromethyl)phenyl]-4-nitropentanoate

Ethyl 3-[3,5-bis(trifluoromethyl)phenyl]acrylate (170 mg, 0.54 mmol) andnitromethane (736 uL, 10.29 mmol) were treated with a solution oftetrabutylammonium hydroxide (1.0 M solution in MeOH, 1.5 mL) and themixture heated to reflux for 3 h, diluted with 10% aqueous ammoniumchloride (10 mL) and extracted with EtOAC (4×30 mL). The combinedorganic extracts were washed with 10% ammonium chloride (20 mL), driedover MgSO₄, concentrated in vacuo to give the crude product. This waspurified by flash chromatography using 10% EtOAC/hexanes to affordmethyl 3-[3,5-bis(trifluoro methyl)phenyl]-4-nitropentanoate as acolorless oil. ¹H NMR (CDCl₃, 500 MHz) δ 7.82 (br s 1H), 7.64 (br s,2H), 4.91 (m, 1H), 3.91 (m, 1H), 3.61 (s, 3H), 2.82 (m, 2H), 1.42 (d,J=6.7 Hz, 3H).

Step C: 4-[3,5-bis(trifluoromethyl)phenyl]-5-methylpyrollidin-2-one

A suspension of Raney Nickel (50% w/v slurry in H₂O, 200 mg) was addedto a solution of methyl3-[3,5-bis(trifluoromethyl)phenyl]-4-nitropentanoate in absolute EtOH (5mL) and the resultant mixture was stirred at room temperature overnightunder a balloon atmosphere of H₂. The reaction mixture was filteredthrough a pad of Celite and the filtrate was concentrated in vacuo toremove the EtOH. The residue was purified by flash chromatography using75% EtOAC/hexanes to affordthreo-4-[3,5-bis(trifluoromethyl)phenyl]-5-methylpyrollidin-2-one anderythro-4-[3,5-bis(trifluoromethyl)phenyl]-5-methylpyrollidin-2-one aswhite solids. erythro-diastereomer: LCMS 353 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.82 (br s 1H), 7.64 (br s, 2H), 5.72 (br s, 1H), 3.85 (m, 1H),3.31 (dd, J=8.9, 8.2 Hz, 1H), 2.61 (dd, J=8.9, 8.2 Hz, 1H), 1.34 (d,J=6.1 Hz, 3H). erythro-diastereomer: LCMS 353 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 7.82 (br s 1H), 7.64 (br s, 2H), 5.76 (br s, 1H), 4.20 (m, 1H),3.90 (m, 1H), 2.81 (dd, J=8.5, 8.2 Hz, 1H), 2.73 (dd, J=8.5, 8.2 Hz,1H), 0.88 (d, J=6.7 Hz, 3H).

Step D:(4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[4′-fluoro-5′-isopropyl]-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-pyrolidin-2-one

To a stirred suspension of NaH (60% in oil, 4.4 mg, 0.11 mmol) in THF (3mL), was added a solution oferythro-4-[3,5-bis(trifluoromethyl)phenyl]-5-methylpyrollidin-2-one (16mg, 0.051 mmol) in THF (1 mL) at 0° C. under an atmosphere of nitrogen.The resultant mixture was allowed to stir for 30 min at 0° C. before theaddition of2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl(16 mg, 0.051 mmol). After 3 h, the reaction was diluted with 15 mLEtOAc and 5 mL H₂O. The phases were separated and the organic phase waswashed with H₂O, brine, dried (MgSO₄), and concentrated. The residue waspurified by flash chromatography using 10% EtOAC/hexanes to afford thetitle compound as a colorless oil. LCMS 636 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) (atropisomers present) ¹H NMR δ 7.82 (br s 1H), 7.80 (br s, 1H),7.45-7.36 (m, 3H), 7.32-7.22 (m, 3H), 7.08 (d, J=10.1 Hz, 1H), 6.60 (m,1H), 5.05 (m, 1H), 4.01 (d, J=15.5 Hz), 3.78 (s, 3H), 3.71-3.52 (m, 2H),3.24 (m, 1H), 1.32-1.20 (m, 6H), 0.56 (d, J=6.4 Hz, 3H). This compoundwas separated into its two enantiomers(4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[4′-fluoro-5′-isopropyl]-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-pyrrolidin-2-oneand(4S,5R)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[4′-fluoro-5′-isopropyl]-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-pyrrolidin-2-oneusing chiral HPLC (IA column, 20×250 mm, 3% i-PrOH in heptane).

Following the general procedures outlined above, the compounds in Table17 were prepared:

TABLE 17

LCMS Example R (M + 1)⁺ 322

534.2 323

534.2 324

584.2 325

568.1 326

568.1

Example 327

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-6-methyl-4-(trifluoromethyl)biphenyl-2-yl]-methyl}-4-methyl-1,3-oxazolidin-2-oneStep A: [2,6-dimethyl-4-(trifluoromethyl)phenyl]amine

A mixture of 2,6-dibromo-4-trifluoromethyl aniline (1.00 g, 3.14 mmol),trimethylboroxin (1.16 ml, 1.04 g, 8.33 mmol), potassium carbonate (1.15g, 8.33 mmol) and catalytic amount (10%) Pd(PPh₃)₄ in DMF (5 ml) washeated to 90° C. for 14 h. Water (10 ml) was added. The mixture wasextracted with ethyl acetate (3×20 ml). The combined EtOAc layers werewashed with brine and dried over sodium sulfate. The titled compound wasobtained as a colorless oil after a flash column using EtOAc:hexane(1:9) as the elute. ¹H NMR (CDCl₃, 500 MHz): δ 7.28 (s, 1H), 7.22 (s,1H), 3.88 (br s, 2H), 2.21 (s, 6H).

Step B: 2-iodo-1,3-dimethyl-5-(trifluoromethyl)benzene

A mixture of the titled compound from Step A (0.27 g, 1.43 mmol),n-pentyl nitrite (0.50 g, 2.86 mmol) and I₂ (0.72 g, 2.86 mmol) inchloroform (10 ml) was refluxed for 1 h. The mixture was diluted withmethylene chloride (20 ml) and washed with saturated sodium thiosulfatesolution, and brine. The organic layer was dried over sodium sulfate.The titled compound was obtained as a light yellow liquid after flashcolumn using hexane as the elute. ¹H NMR (CDCl₃, 500 MHz) δ 7.31 (s,2H), 2.58 (s, 6H).

Step C: 1-(bromomethyl)-2-iodo-3-methyl-5-(trifluoromethyl)benzene

A mixture of the titled compound from Step B (0.26 g, 0.87 mmol), NBS(0.154 g, 0.87 mmol) and catalytic amount of AIBN in CCl₄ was refluxedfor 6 h. TLC (hexane) showed a mixture of starting material and a newspot. Upon addition of more AIBN the reaction was allowed to reflux foranother 2 h. No change was observed. The reaction mixture was cooled toroom temperature and the solvent was removed. The titled compound wasobtained as a white solid along with the starting material afterpreparative TLC purification using hexane as the elute. ¹H NMR (CDCl₃,500 MHz): δ 7.54 (s, 1H), 7.42 (s, 1H), 4.67 (s, 2H), 2.60 (s, 3H).

Step D.(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-3-methyl-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of oxazolidone from Example xx, step xx, (0.058 g, 0.186mmol) in THF (5 ml) at 0° C., NaH was added. The mixture was stirred for30 min at 0° C. A solution of benzyl bromide from Step C (0.064 g, 0.169mmol) in THF (5 ml) was added via syringe. The mixture was then allowedto stirred at room temperature for 12 h. The reaction was quenched withsaturated ammonium chloride solution. The mixture was extracted withethyl acetate (3×15 ml). The combined EtOAc layers were washed withbrine and dried over sodium sulfate. The titled compound was obtainedafter a preparative TLC plate using EtOAc:hexane=1:9 as the elute. ¹HNMR (CDCl₃, 500 MHz): δ 7.92 (s, 1H), 7.82 (s, 2H), 7.49 (s, 1H), 7.38(s, 1H), 5.77 (d, J=8 Hz, 1H), 4.93 (d, J=16 Hz, 1H), 4.45 (d, J=16 Hz,1H), 4.05 (m, 1H), 2.60 (s, 3H), 0.81 (d, J=6.5 Hz, 3H).

Step E:(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-6-methyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

A mixture of the titled compound from Step D (0.07 g, 0.11 mmol),2-methoxy-4-fluoro-5-isopropyl phenyl boronic acid (0.036 g, 0.17 mmol),sodium carbonate (0.024 g, 0.23 mmol) and catalytic amount of Pd(PPh₃)₄in a mixture of 2:1:4 EtOH/H₂O/toluene was heated to reflux for 3 h. Thesolvents were removed and the aqueous was extracted with methylenechloride (3×20 ml). The combined methylene chloride layers were washedwith brine, and dried over sodium sulfate. The titled compound wasobtained after a preparative TLC plate using EtOAc:hexane=1:9 as theelute. Two diastereomeric atropisomers of the titled compound wereseparated by a chiral OD column using EtOH/n-Heptane as the elute.Isomer A (faster elute): ¹H NMR (CDCl₃, 500 MHz): δ 7.89 (s, 1H), 7.75(s, 2H), 7.52 (s, 2H), 6.85 (d, J=8.5 Hz, 1H), 6.71 (d, J=12 Hz, 1H),5.63 (d, J=8 Hz, 1H), 4.71 (d, J=16 Hz, 1H), 3.93 (m, 1H), 3.87 (d, J=16Hz, 1H), 3.72 (s, 3H), 3.22 (m, 1H), 2.09 (s, 3H), 1.26 (m, 6H), 0.53(d, J=6.5 Hz, 3H); LC-MS (M+1): 652.3. Isomer B (slower elute): ¹H NMR(CDCl₃, 500 MHz): δ 7.89 (s, 1H), 7.73 (s, 2H), 7.53 (s, 2H), 6.90 (d,J=8.5 Hz, 1H), 6.73 (d, J=12 Hz, 1H), 5.60 (d, J=8 Hz, 1H), 4.69 (d,J=15.5 Hz, 1H), 3.88 (m, 1H), 3.86 (d, J=15.5 Hz, 1H), 3.76 (s, 3H),3.22 (m, 1H), 2.11 (s, 3H), 1.23 (m, 6H), 0.48 (d, J=6.5 Hz, 3H); LC-MS(M+1): 652.3.

Example 328

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-chloro-4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-oneStep A: [2-chloro-6-methyl-4-(trifluoromethyl)phenyl]amine

A mixture of 2-bromo-6-chloro-4-trifluoromethyl aniline (1.00 g, 3.64mmol), trimethylboroxin (0.66 ml, 0.59 g, 4.47 mmol), potassiumcarbonate (1.00 g, 7.30 mmol) and catalytic amount (10%) Pd(PPh₃)₄ inDMF (5 ml) was heated to 90° C. for 14 h. Water (20 ml) was added. Themixture was extracted with ethyl acetate (3×50 ml). The combined EtOAclayers were washed with brine and dried over sodium sulfate. The titledcompound was obtained as a colorless oil after a flash column usingEtOAc:hexane (1:9) as the elute. ¹H NMR (CDCl₃, 500 MHz): δ 7.43 (s,1H), 7.24 (s, 1H), 4.38 (br s, 2H), 2.22 (s, 3H).

Step B [2-chloro-6-(iodomethyl)-4-(trifluoromethyl)phenyl]amine

A mixture of the titled compound from Step A (0.67 g, 3.20 mmol),n-pentyl nitrite (0.75 g, 6.41 mmol) and I₂ (1.05 g, 4.17 mmol) inchloroform (10 ml) was refluxed for 1 h. The mixture was diluted withmethylene chloride (20 ml) and washed with saturated sodium thiosulfatesolution, and brine. The organic layer was dried over sodium sulfate.2-Iodo-3-chloro-4-trifluoromethyl benzyl iodide were obtained as afterflash column using hexane as the elute. ¹H NMR (CDCl₃, 500 MHz): δ 7.60(s, 2H), 4.65 (s, 2H).

Step C.(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[3-chloro-2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of oxazolidone from Example xx, step xx, (0.058 g, 0.186mmol) in THF (5 ml) at 0° C., NaH was added. The mixture was stirred for30 min at 0° C. A solution of 2-iodo-3-chloro-4-trifluoromethyl benzyliodide from Step B (0.226 g, 0.51 mmol) in THF (5 ml) was added viasyringe. The mixture was then allowed to stir at room temperature for 3h. The reaction was quenched with saturated ammonium chloride solution.The mixture was extracted with ethyl acetate (3×20 ml). The combinedEtOAc layers were washed with brine and dried over sodium sulfate. Thetitled compound was obtained after a flash column using EtOAc:hexane=1:9as the elute. LC-MS (M+1): 432.0.

Step D:(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-chloro-4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

A mixture of the titled compound from Step C (0.10 g, 0.16 mmol),2-methoxy-4-fluoro-5-isopropyl phenyl boronic acid (0.067 g, 0.32 mmol),sodium carbonate (0.034 g, 0.32 mmol) and catalytic amount of Pd(PPh₃)₄in a mixture of 2:1:4 EtOH/H2O/toluene was heated to reflux for 4 h. Thesolvents were removed and the aqueous was extracted with methylenechloride (3×15 ml). The combined methylene chloride layers were washedwith brine, and dried over sodium sulfate. The titled compound wasobtained after a preparative TLC plate using EtOAc:hexane=1:9 as theelute. Two diastereomeric atropisomers of the titled compound wereseparated by a chiral AD column using i-PrOH/n-Heptane as the elute.Isomer A (faster elute): ¹H NMR (CDCl₃, 500 MHz): δ 7.91 (s, 1H), 7.75(s, 3H), 7.61 (s, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.73 (d, J=12 Hz, 1H),5.64 (d, J=8 Hz, 1H), 4.72 (d, J=16 Hz, 1H), 3.95 (d, J=16 Hz, 1H), 3.93(m, 1H), 3.78 (s, 3H), 3.22 (m, 1H), 1.23 (m, 6H), 0.55 (d, J=7 Hz, 3H);LC-MS (M+1): 672.1. Isomer B (slower elute): ¹H NMR (CDCl₃, 500 MHz): δ7.89 (s, 1H), 7.75 (s, 1H), 7.73 (s, 2H), 7.62 (s, 1H), 6.98 (d, J=8.5Hz, 1H), 6.74 (d, J=12 Hz, 1H), 5.61 (d, J=8.5 Hz, 1H), 4.72 (d, J=16Hz, 1H), 3.91 (d, J=16 Hz, 1H), 3.87 (m, 1H), 3.79 (s, 3H), 3.22 (m,1H), 1.22 (m, 6H), 0.48 (d, J=6.5 Hz, 3H); LC-MS (M+1): 672.1.

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(2.0 g, 6.39 mmol) in THF (40 mL) at 0° C., NaH (285 mg, 60 w/w % inmineral oil, 7.13 mmol, 1.1 eq.) was added in one portion. The resultingfoaming mixture was stirred in an ice bath. Additional THF (50 mL) wasadded into the reaction. The mixture was stirred at 0° C. for 30 min. Asolution of 2-bromo-5-fluorobenzyl bromide (1.712 g, 6.39 mmol) in THF(20 mL) was added. The resulting mixture was stirred cold for 30 min andthen allowed to warm to ambient. The reaction was completed in 3 h,monitored by LC-MS. The reaction was quenched with saturated aq. NH₄Cl(80 mL). Volatiles were removed in vacuo. Crude mixture was extractedwith EtOAc, and dried over Na₂SO₄. The resulting clear gel was purifiedby SiO₂ (Biotage 40+M cartridge, EtOAc/hexane, gradient). The titledcompound was obtained as a clear oil. LC-MS: 500.09 (M+1)⁺. ¹H NMR(CDCl₃, 500 MHz) δ 7.88 (s, 1H), 7.79 (s, 2H), 7.55 (dd, J=8.8, 5.2 Hz,1H), 7.17 (dd, J=8.7, 4.5 Hz, 1H), 6.95 (m, 1H), 5.74 (d, J=8.0 Hz, 1H),4.83 (d, J=15.8, 1H), 4.54 (d, J=16.0 Hz, 1H), 4.11 (m, 1H), 0.80 (d,J=6.6 Hz, 3H).

Example 329

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4,4′-difluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one(1.0 g, 2.0 mmol) in 1,4-dioxane (6 mL) was added(4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (509 mg, 2.4 mmol),[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (II) (82 mg, 5mol %) and aq. potassium hydroxide (1.3 mL, 3M, 2 eq.). The reactionmixture was purged with nitrogen and then sealed in a microwave vessel.The reaction vessel was subject to microwave irradiation at 150° C. for40 min. Crude mixture was worked up with water. Volatiles wereevaporated. The resulting mixture was extracted with EtOAc. The combinedextracts were dried over Na₂SO₄. The resulting purple residue waspurified by SiO₂ (Biotage 40+M cartridge, eluted by EtOAc/hexane,gradient; 5% to 25%). The titled compound was obtained as clear solid.LC-MS: 588.23 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 6:4 mixture of rotamersδ 7.85 (s, 1H), 7.69 (s, 2H), 7.16-7.21 (m, 1.5H), 7.04-7.13 (m, 1.5H),6.96 (dd, J=14.3, 8.80 Hz, 1H), 6.65 (d, J=10.0 Hz, 1H), 5.59 (d, J=8.0Hz, 0.6H), 5.43 (d, J=8.0 Hz, 0.4H), 4.85 (d, J=15.8 Hz, 0.6H), 4.82 (d,J=15.8 Hz, 0.4H), 4.02 (d, J=15.8 Hz, 0.6H), 3.85 (m, 0.6H), 3.76-3.81(m, 0.8H), 3.75 (s, 1.8H), 3.73 (s, 1.2H), 3.19 (m, 1H), 1.14-1.26 (m,6H), 0.56 (d, J=6.6 Hz, 1.2H), 0.38 (d, J=6.6 Hz, 1.8H).

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-chloro-4-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(1.0 g, 3.19 mmol)/THF (40 mL) at 0° C., was added NaH (153 mg, 60 w/w %in mineral oil, 3.83 mmol, 1.2 eq.) in one portion. The resultingfoaming mixture was stirred in an ice bath for 30 min, followed byaddition of 2-chloro-4-fluorobenzyl chloride (572 mg, 3.19 mmol). Theresulting mixture was stirred at 0° C. for 30 min then warmed to ambientovernight. The reaction failed to proceed at room temperature and it waswarmed in a 60° C. oil bath for 20 h. An aliquot indicated that thereaction was over. It was quenched with aq. NH₄Cl (50 mL). Volatileswere evaporated. The resulting mixture was extracted with EtOAc. Thecombined extracts were dried over Na₂SO₄, filtered and concentrated invacuo to a yellow oil. The oil was purified by SiO₂ (Biotage 40+Mcartridge, eluted by EtOAc/hexanes, gradient; 5% to 40%). The titledcompound was obtained as a colorless glassy material. LC-MS: 456.12(M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.89 (s, 1H), 7.77 (s, 2H), 7.46 (dd,J=8.7, 6.0 Hz, 1H), 7.17 (dd, J=8.4, 2.5 Hz, 1H), 7.03 (m, 1H), 5.68 (d,J=8.2 Hz, 1H), 4.83 (d, J=15.6, 1H), 4.36 (d, J=15.3 Hz, 1H), 4.06 (m,1H), 0.79 (d, J=6.4 Hz, 3H).

Example 330

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4′,5-difluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-chloro-4-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one(100 mg, 0.22 mmol) in 1,4-dioxane (1 mL) was added(4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (55.8 mg, 0.26 mmol),palladium(II) acetate (10 mg, 20 mol %), potassium hydroxide aqueoussolution (147 μL, 3M, 2 eq.) and tri-tert-butylphosphine (13.4 mg, 0.066mmol, 30 mol % as a 10% w/w hexane solution). The resulting reactionmixture was N₂ purged and sealed in a microwave vessel. The vessel wassubject to microwave irradiation at 140° C. for 40 min. LC-MS indicatedthe formation of desired product. It was quenched with water (50 mL).Volatiles were evaporated. The resulting mixture was extracted withEtOAc. The combined extracts were dried over Na₂SO₄, filtered andconcentrated in vacuo to an oil. The titled compound was obtained aftertwo purifications with silica gel and one reversed phase prep-HPLC.LC-MS: 588.25 (M+1)⁺.

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-chloro-6-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(1.0 g, 3.19 mmol) in THF (40 mL) at 0° C., was added NaH (153 mg, 60w/w % in mineral oil, 3.83 mmol, 1.2 eq.) in one portion. The resultingfoaming mixture was stirred in an ice bath for 30 min followed byaddition of benzyl chloride (572 mg, 3.19 mmol). The resulting mixturewas stirred at 0° C. for 30 min then warmed to 60° C. for 30 hr. Analiquot indicated about 10% of starting(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-oneleft. The reaction was cooled and quenched with saturated NH₄Cl (50 mL).Volatiles were evaporated. The resulting mixture was extracted withEtOAc. The combined extracts were dried over Na₂SO₄, filtered andconcentrated in vacuo to a yellow oil. The titled compound was obtainedas a colorless glassy material after purification by SiO₂ (Biotage 40+M,eluted by EtOAc/hex, gradient; 5% to 40%). LC-MS: 456.11 (M+1)⁺. ¹H NMR(CDCl₃, 500 MHz) δ 7.87 (s, 1H), 7.77 (s, 2H), 7.22-7.34 (m, 2H),7.01-7.09 (m, 1H), 5.62 (d, J=8.2 Hz, 1H), 5.01 (dd, J=14.8, 2.0 Hz,1H), 4.45 (d, J=14.6 Hz, 1H), 3.91 (m, 1H), 0.81 (d, J=6.4 Hz, 3H).

Example 331

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3,4′-difluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-chloro-6-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one(327 mg, 0.72 mmol) in 1,4-dioxane (4 mL) was added(4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (228 mg, 1.08 mmol),Palladium(II) acetate (33 mg, 20 mol %), potassium hydroxide (588 μL,3M, 2.5 eq.) and tri-tert-butylphosphine (44 mg, 0.22 mmol, 30 mol % asa 10% w/w hexane solution). The resulting reaction mixture was purgedwith nitrogen and sealed in a microwave vessel. The vessel was subjectto microwave irradiation at 135° C. for 50 min. LC-MS indicated thestarting material/product ratio was about 55:45. The reaction mixturewas re-submitted to reaction conditions (μw at 135° C. for 50 min). TheLC-MS trace indicated that no progress was made from the 2^(nd)irradiation. More palladium(II) acetate (33 mg, 20 mol %) andtri-tert-butylphosphine (44 mg, 0.22 mmol, 30 mol % as a 10% w/w hexanesolution) were added into reaction mixture. The mixture was resubmittedto reaction conditions (μw at 135° C., 1 hr). Again, the LC-MS indicatedno significant progress. The reaction mixture was quenched with H₂O. Thevolatiles were removed under reduced pressure. The resulting mixture wasextracted with EtOAc. The combined extracts were dried over Na₂SO₄,filtered and concentrated in vacuo to a yellow oil. The oil wasdissolved in DMSO and purified twice by a reversed phase prep-HPLC(column: Kromasil, 100-5C18, 100×21.1 mm) eluted by 10% to 90% H₂O (0.1%TFA, v/v)/MeCN (0.1% TFA, v/v). The resulting glassy material was thenpurified on a prep-TLC plate by 100% dichloromethane to afford thetitled compound. LC-MS: 588.21 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 1:1mixture of rotamers δ 7.83 (s, 1H), 7.67 (s, 1H) 7.65 (s, 1H), 7.32-7.41(m, 1H), 7.09-7.16 (m, 1H), 6.96-7.06 (m, 1H), 6.64-6.70 (m, 1H), 5.47(d, J=8.0 Hz, 0.5H), 5.19 (d, J=7.8 Hz, 0.5H), 4.96 (d, J=14.9 Hz,0.5H), 4.80 (d, J=15.1 Hz, 0.5H), 4.31 (d, J=15.1 Hz, 0.5H), 3.91 (d,J=15.1 Hz, 0.5H), 3.78 (s, 1.5H), 3.75 (s, 1.5H), 3.62-3.69 (m, 1H),3.15-3.26 (m, 1H), 1.14-1.25 (m, 6H), 0.54 (d, J=6.6 Hz, 1.5H), 0.33 (d,J=6.4 Hz, 1.5H).

Example 332

Step A: 2-bromo-5-nitrophenyl)methanol

Methyl 2-bromo-5-nitrobenzoate (10 g, 38.46 mmol) was dissolved in THF(100 mL) and cooled to internal temperature=−15˜−10° C. To this mixturewas added diisobutylaluminum hydride solution (1.0 M in toluene, 57 mL,57 mmol) slowly while maintaining internal temperature <0° C. Theresulting mixture was stirred at ambient for 1 hour then quenched withaq. NH₄Cl (150 mL). The crude mixture was diluted with EtOAc (100 mL)and then filtered. Volatiles were removed under reduced pressure. Theresulting residue was extracted with EtOAc (200 mL×2). The combinedextracts were dried over Na₂SO₄, filtered and evaporated to an oil. Theresulting oil was purified by SiO₂ (Biotage 65i, EtOAc/hexanes,gradient; 10% to 15%). The titled compound was obtained as a yellowcrystalline solid. ¹H NMR (CDCl₃, 500 MHz) δ 8.44 (d, J=2.74 Hz 1H),8.02 (dd, J=8.7, 2.8 Hz, 1H), 7.72 (d, J=8.7, 1H), 4.83 (s, 3H).

Step B: 1-bromo-2-(bromomethyl)-4-nitrobenzene

To a solution of 2-bromo-5-nitrophenyl)methanol (4.746 g, 20.45 mmol) inanhydrous dichloromethane (150 mL), was added triphenylphosphine (6.43g, 24.5 mmol) and carbon tetrabromide (8.15 g, 24.5 mmol). The mixturewas stirred at 0° C. for 30 min then at 20° C. for 1 h. TLC showedcomplete consumption of starting material. Volatiles were removed underreduced pressure. The resulting oil was purified by SiO₂ (Biotage 40M,eluted by EtOAc/hexanes, gradient) to afford the titled compound as acolorless solid. ¹H NMR (CDCl₃, 500 MHz) δ 8.33 (d, J=2.74 Hz 1H), 8.03(dd, J=8.7, 2.5 Hz, 1H), 7.78 (d, J=8.7, 1H), 4.63 (s, 3H).

Step C:(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(5.3 g, 16.95 mmol) in THF (100 mL) at 0° C., NaH (746 mg, 60 w/w % inmineral oil, 18.65 mmol, 1.1 eq.) was added in one portion. Theresulting foaming mixture was stirred in an ice bath. Additional THF(100 mL) was added into the reaction. The mixture was stirred at 0° C.for 30 min. A solution of 1-bromo-2-(bromomethyl)-4-nitrobenzene (5.0 g,16.95 mmol) in THF (25 mL) was added. The resulting mixture was stirredcold for 30 min and then allowed to warm to ambient. The reaction wascompleted in 1.5 h. The reaction was quenched with sat. aqueous NH₄Cl(100 mL). Crude mixture was extracted with EtOAc, and dried over Na₂SO₄.The resulting clear gel was purified by SiO₂ (Biotage 40M cartridge,EtOAc/hexane, gradient, 25% to 45%). The titled compound was obtained asa crystalline solid. LC-MS: 529.11 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ8.24 (d, J=2.5 Hz, 1H), 8.07 (dd, J=8.7, 2.8 Hz, 1H), 7.91 (s, 1H),7.79-7.83 (m, 3H), 5.82 (d, J=7.8 Hz, 1H), 4.82 (d, J=16.2 Hz, 1H), 4.44(d, J=16.3, 1H), 4.11-4.20 (m, 1H), 0.84 (d, J=6.6 Hz, 3H).

Step D:(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4′-fluoro-5′-isopropyl-2′-methoxy-4-nitrobiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl-1,3-oxazolidin-2-one(3.877 g, 7.35 mmol) in a toluene (24 mL): ethanol (12 mL): water (6 mL)mixture was added (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid(2.337 g, 11.03 mmol), tetrakis (triphenylphosphine) palladium(0) (425mg, 5 mol %) and sodium carbonate (1.56 g, 14.72 mmol). The resultingmixture was bubbled with nitrogen and then heated in a 90° C. oil bathfor 10 h. An aliquot showed complete consumption of the startingmaterial. The reaction was quenched with brine. The resulting mixturewas extracted with EtOAc and dried over Na₂SO₄. The resulting glassymixture was purified by SiO₂ (Biotage 40S cartridge, EtOAc/hexane,gradient). The titled compound was obtained as a crystalline solid.LC-MS: 615.26 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 1:1 mixture of rotamersδ 8.31 (s, 1H), 8.20-8.26 (m, 1H), 7.86 (s, 1H), 7.70 (s, 2H), 7.39-7.43(m, 1H), 6.96-7.01 (m, 1H), 6.67-6.72 (m, 1H), 5.64 (d, J=8.0 Hz, 0.5H),5.48 (d, J=8.0 Hz, 0.5H), 4.90 (d, J=16.3 Hz, 0.5H), 4.86 (d, J=16.3 Hz,0.5H), 4.10-4.16 (m, 0.5H), 3.84-3.94 (m, 1.5H), 3.77 (s, 1.5H), 3.75(s, 1.5H), 3.15-3.26 (m, 1H), 1.15-1.29 (m, 6H), 0.57 (d, J=6.6 Hz,1.5H), 0.40 (d, J=6.6 Hz, 1.5H).

Example 333

(4S,5R)-3-[(4-amino-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

A solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4′-fluoro-5′-isopropyl-2′-methoxy-4-nitrobiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one(1.94 g, 3.16 mmol) in methanol (20 mL) was subject to H₂ (40 psi., Parrshaker) at 20° C. for 1.5 h. LCMS indicated the presence of tracestarting material. The crude mixture was filtered through a bed ofCelite (521). The filtrate was evaporated in vacuo to afford a glass asthe product. LC-MS: 585.32 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 1:1 mixtureof rotamers δ 7.83 (s, 1H), 7.67 (s, 2H), 6.93-7.06 (m, 2H), 6.87 (s,0.5H), 6.72-6.82 (m, 1.5H), 5.57 (d, J=8.0 Hz, 0.5H), 5.36 (d, J=8.0 Hz,0.5H), 4.77 (d, J=5.5 Hz, 0.51-1), 4.74 (d, J=6.5 Hz, 0.5H), 3.95 (d,J=15.5 Hz, 0.5H), 3.75-3.86 (m, 1.5H), 3.73 (s, 3H), 3.12-3.24 (m, 1H),1.11-1.29 (m, 6H), 0.47 (d, J=6.5 Hz, 1.5H), 0.29 (d, J=6 Hz, 1.5H).

Example 334

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To a solution(4S,5R)-3-[(4-amino-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(526 mg, 0.90 mmol) in bromoform (2.5 mL) was added tert-butyl nitrite(186 mg, 1.80 mmol). The resulting mixture was stirred at 80° C. for 20min. An aliquot indicated completion of the reaction. The reaction crudewas purified silica gel to afford the title compound as a yellow glass.LC-MS: 650.09 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 1:1 mixture of rotamersδ 7.85 (s, 1H), 7.69 (s, 2H), 7.60 (s, 0.5H), 7.48-7.53 (m, 1.5H),7.07-7.11 (m, 1H), 6.93-6.99 (m, 1H), 6.62-6.67 (m, 1H), 5.59 (d, J=8.0Hz, 0.5H), 5.39 (d, J=7.0 Hz, 0.5H), 4.82 (d, J=6.5 Hz, 0.5H), 4.75 (d,J=6.5 Hz, 0.5H), 3.98 (d, J=16.0 Hz, 0.5H), 3.76-3.85 (m, 1.5H), 3.75(s, 1.5H), 3.74 (s, 1.5H), 3.13-3.23 (m, 1H), 1.13-1.29 (m, 6H), 0.52(d, J=6.5 Hz, 1.5H), 0.34 (d, J=7.0 Hz, 1.5H).

Example 335

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-cyclopropyl-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one(100 mg, 0.15 mmol) in 1,4-dioxane (0.5 mL) was added cyclopropylboronicacid (10 mg, 0.19 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (82 mg, 8mol %), bis(tri-tert-butylphosphine)palladium (0) (10 mg, 13 mol %) andaqueous potassium hydroxide (78 μL, 3M, 1.5 eq.). The reaction mixturewas purged with nitrogen and then sealed in a microwave vessel. Thereaction vessel was subject to microwave irradiation at 150° C. for 30min. An aliquot indicated complete consumption of starting material.Reaction crude was worked up with water. The resulting mixture wasextracted with EtOAc and dried over Na₂SO₄. The titled compound wasobtained as a glassy material after two preparative TLC plates usingrespectively 20% EtOAc in hexanes and 5% EtOAc in dichloromethane as theeluent. LC-MS: 610.26 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 1:1 mixture ofrotamers δ 7.84 (s, 1H), 7.65-7.70 (m, 2H), 7.21 (s, 0.5H), 7.08-7.14(m, 1.5H), 6.95-7.04 (m, 2H), 6.61-6.67 (m, 1H), 5.52 (d, J=8.5 Hz,0.5H), 5.27 (d, J=8.0 Hz, 0.5H), 4.85 (d, J=15.5 Hz, 0.5H), 4.81 (d,J=15.5 Hz, 0.5H), 4.00 (d, J=15.5 Hz, 0.5H), 3.69-3.81 (m, 4.5H),3.13-3.24 (m, 1H), 1.90-1.99 (m, 1H), 1.12-1.30 (m, 6H), 0.98-1.15 (m,2H), 0.71-0.77 (m, 2H), 0.48 (d, J=6.5 Hz, 1.5H), 0.29 (d, J=6.5 Hz,1.5H).

Example 336

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(methylthio)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

To a solution(4S,5R)-3-[(4-amino-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(200 mg, 0.34 mmol) in methyl disulfide (2 mL) was added tert-butylnitrite (70 mg, 0.68 mmol). The resulting mixture was stirred at 80° C.for 30 min. An aliquot indicated completion of the reaction. The titledcompound was obtained as a glassy material after two preparative TLCplates using respectively 20% EtOAc in hexanes and 10% EtOAc indichloromethane as the eluent. LC-MS: 616.21 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) δ 1:1 mixture of rotamers δ 7.84 (s, 1H), 7.67 (s, 2H), 7.35 (s,0.5H), 7.22-7.28 (m, 1.5H), 7.12-7.19 (m, 1H), 6.94-7.02 (m, 1H),6.61-6.68 (m, 1H), 5.55 (d, J=8.0 Hz, 0.5H), 5.31 (d, J=9.5 Hz, 0.5H),4.85 (d, J=16.0 Hz, 0.5H), 4.83 (d, J=15.5 Hz, 0.5H), 3.99 (d, J=15.5Hz, 0.5H), 3.69-3.81 (m, 4.5H), 3.12-3.24 (m, 1H), 2.54, (s, 1.5H), 2.53(s, 1.5H), 1.11-1.27 (m, 6H), 0.50 (d, J=6.5 Hz, 1.5H), 0.31 (d, J=7.0Hz, 1.5H).

Example 337

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(methylsulfonyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(methylthio)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one(156 mg, 0.25 mmol) in dichloromethane (3 mL) was added3-chloroperbenzoic acid (175 mg, 1.01 mmol). The resulting mixture wasstirred at 20° C. for 1 h. An aliquot indicated completion of thereaction. Reaction crude was partitioned between water anddichloromethane. The organic layer was separated and dried over Na₂SO₄.The titled compound was obtained as a glassy material after threepreparative TLC plates using respectively 50% EtOAc in hexanes, 20%EtOAc in dichloromethane and dichloromethane as the eluent. LC-MS:648.29 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 1:1 mixture of rotamers δ 7.99(s, 0.5H), 7.92-7.96 (m, 1.5H), 7.86 (s, 1H), 7.70 (s, 2H), 7.42-7.46(m, 1H), 6.96-7.00 (m, 1H), 6.69 (d, J=12 Hz, 1H), 5.64 (d, J=8.0 Hz,0.5H), 5.45 (d, J=8.0 Hz, 0.5H), 4.93 (d, J=6.0 Hz, 0.5H), 4.90 (d,J=6.5 Hz, 0.5H), 4.09 (d, J=16 Hz, 0.5H), 3.88 (d, J=16 Hz, 0.5H),3.80-3.88 (m, 1H), 3.78 (s, 1.5H), 3.75 (s, 1.5H), 3.16-3.25 (m, 1H),3.14 (s, 1.5H), 3.13 (s, 1.5H), 1.22-1.28 (m, 6H), 0.57 (d, J=6.5 Hz,1.5H), 0.38 (d, J=6.5 Hz, 1.5H).

Example 338

2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-4-carbonitrile

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one(100 mg, 0.15 mmol) in N,N-dimethylformamide (1.5 mL) was addedcopper(I) cyanide (17 mg, 0.19 mmol). The resulting reaction mixture wasN₂ purged and sealed in a microwave vessel. The vessel was subject tomicrowave irradiation at 150° C. for 30 min. LC-MS indicated only thestarting bromide was present. Addedtetrakis(triphenylphosphine)palladium(0) (10 mg, 6 mol %) into thereaction mixture. Repeated microwave irradiation at 150° C. for 30 min.An aliquot indicated the desired product was formed and all startingbromide was consumed. Reaction crude was partitioned between water andhexanes. The aqueous phase was back extracted with diethyl ether. Thecombined extracts were dried over Na₂SO₄. The titled compound wasobtained as a glassy material after two preparative TLC plates developedrespectively by 20% EtOAc in hexanes and 4% EtOAc in dichloromethane.LC-MS: 595.03 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 1:1 mixture of rotamersδ 7.86 (s, 1H), 7.61 (S, 0.5H), 7.67-7.71 (m, 2.5H), 7.64-7.68 (m, 1H),7.32-7.36 (m, 1H), 6.98 (d, J=8.5 Hz, 0.5H), 6.95 (d, J=8.5 Hz, 0.5H),6.68 (d, J=12 Hz, 1H), 5.62 (d, J=8.0 Hz, 0.5H), 5.46 (d, J=8.0 Hz,0.5H), 4.85 (d, J=16.0 Hz, 0.5H), 4.80 (d, J=16.0 Hz, 0.5H), 4.06 (d,J=16 Hz, 0.5H), 3.79-3.86 (m, 1H), 3.70-3.78 (m, 3.5H), 3.16-3.24 (m,1H), 3.75 (s, 1.5H), 3.16-3.25 (m, 1H), 3.14 (s, 1.5H), 3.13 (s, 1.5H),1.15-1.27 (m, 6H), 0.54 (d, J=7.0 Hz, 1.5H), 0.37 (d, J=6.5 Hz, 1.5H).

Example 339

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4′-fluoro-5′-isopropyl-2′-methoxy-4-methylbiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one(82.5 mg, 0.13 mmol) in 1,4-dioxane (1 mL) was added trimethylboroxin(39 mg, 0.31 mmol), Pd(PPh₃)₄ (15 mg, 10 mol %) and potassium carbonate(35 mg, 0.25 mmol). The resulting reaction mixture was purged withnitrogen and sealed in a microwave vessel. The vessel was subject tomicrowave irradiation at 130° C. for 15 min. The crude mixture wasdiluted with brine and extracted with EtOAc. The combined organicextracts were dried over Na₂SO₄. The titled compound was obtained as aglassy material after two preparative TLC plates developed respectivelyby 20% EtOAc in hexanes and dichloromethane. LC-MS: 584.08 (M+1)⁺. ¹HNMR (CDCl₃, 500 MHz) δ 1:1 mixture of rotamers δ 7.84 (s, 1H), 7.65-7.70(m, 2H), 7.29 (s, 0.5), 7.18-7.22 (m, 1.5H), 7.10-7.15 (m, 1H), 7.01 (d,J=8.0 Hz, 0.5H), 6.98 (d, J=8.5 Hz, 0.5H), 6.66 (d, J=5.0 Hz, 0.5H),6.64 (d, J=5.5 Hz, 0.5H), 5.54 (d, J=8.5 Hz, 0.5H), 5.31 (d, J=8.0 Hz,0.5H), 4.82 (d, J=15.5 Hz, 1H), 4.02 (d, J=15 Hz, 0.5H), 3.71-3.82 (m,5H), 3.15-3.24 (m, 1H), 2.42 (s, 1.5H), 2.41 (s, 1.5H), 1.13-1.27 (m,6H), 0.48 (d, J=6.5 Hz, 1.5H), 0.31 (d, J=6.5 Hz, 1.5H).

Example 340

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4′-fluoro-4-isopropenyl-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one(38 mg, 0.059 mmol) in 1,4-dioxane (0.5 mL) was added(2-chloro-5-isopropylphenyl)boronic acid (10 mg, 0.12 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (2.4 mg, 5mol %) and aqueous potassium hydroxide (40 μL, 3M, 2 eq.). The reactionmixture was purged with nitrogen and then sealed in a microwave vessel.The reaction vessel was subject to microwave irradiation at 140° C. for20 min. Crude mixture was worked up with water and EtOAc. The combinedorganic extracts were dried over Na₂SO₄ and concentrated in vacuo togive the crude product. This was purified by preparative TLC plateeluted by 20% EtOAc in hexanes to give the titled compound. LC-MS:610.04 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 1:1 mixture of rotamers 7.84(s, 1H), 7.64-7.70 (m, 2H), 7.56 (s, 0.5), 7.45-7.50 (m, 1.5H),7.18-7.23 (m, 1H), 7.02 (d, J=9.0 Hz, 0.5H), 6.99 (d, J=8.5 Hz, 0.5H),6.67 (d, J=7.0 Hz, 0.5H), 6.64 (d, J=5.5 Hz, 0.5 H), 5.52 (d, J=8.0 Hz,0.5H), 5.43 (d, J=8.5 Hz, 1H), 5.26 (d, J=8.0 Hz, 0.5H), 5.13-5.17 (m,1H), 4.91 (d, J=15.0 Hz, 0.5H), 4.86 (d, J=15.5 Hz, 0.5H), 4.04 (d,J=15.5 Hz, 0.5H), 3.83 (d, J=15.5, 0.5H), 3.70-3.78 (m, 3H), 3.14-3.25(m, 1H), 2.18-2.22 (m, 3H), 1.14-1.29 (m, 6H), 0.50 (d, J=6.5 Hz, 1.5H),0.31 (d, J=6.5 Hz, 1.5H).

Example 341

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4′-fluoro-4,5′-diisopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

A solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4′-fluoro-4-isopropenyl-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one(15 mg, 0.025 mmol) in methanol (1 mL) was subject to H₂ (balloonatmosphere) at 20° C. overnight. The crude mixture was filtered througha syringe filter. The filtrate was evaporated in vacuo and purified bypreparative TLC plates developed by 20% EtOAc in hexanes to give thetitled compound. LC-MS: 612 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 1:1mixture of rotamers δ 7.84 (s, 1H), 7.64-7.68 (m, 2H), 7.30 (s, 0.5),7.20-7.27 (m, 1.5H), 7.13-7.17 (m, 1H), 7.02 (d, J=8.5 Hz, 0.5H), 6.99(d, J=8.0 Hz, 0.5H), 6.65 (d, J=6.0 Hz, 0.5H), 6.63 (d, J=6.0 Hz, 0.5H),5.52 (d, J=8.0 Hz, 0.5H), 5.25 (d, J=8.0 Hz, 1H), 4.87 (d, J=15.5 Hz,0.5H), 4.82 (d, J=15.5 Hz, 0.5H), 4.03 (d, J=15.0 Hz, 0.5H), 3.81 (d,J=15.0 Hz, 0.5H), 3.69-3.77 (m, 4H), 3.14-3.24 (m, 1H), 2.92-3.02 (m,1H), 1.14-1.33 (m, 12H), 0.48 (d, J=6.5 Hz, 1.5H), 0.30 (d, J=7.0 Hz,1.5H).

(4S,5R)-3-(5-amino-2-bromobenzyl)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

A mixture of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl-1,3-oxazolidin-2-one(614 mg, 1.17 mmol), tin(II) chloride dehydrate (1.314 g, 5.823 mmol)and ethanol (3 mL) was stirred at 20° C. for 36 h. Reaction crude wasworked up with water. The resulting mixture was extracted with EtOAc anddried over Na₂SO₄. The titled compound was obtained as a glassy materialafter SiO₂ purification (Biotage 40+M, gradient, 0% to 35% EtOAc inhexanes). LC-MS: 499.05 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) δ 7.88 (s, 1H),7.77 (s, 2H), 7.31 (d, J=8.5, 1H), 6.77 (d, J=2.7, 1H), 6.54 (dd, J=8.5,2.7 Hz, 1H), 5.69 (d, J=8.0 Hz, 1H), 4.77 (d, J=15.3, 1H), 4.29 (d,J=15.3 Hz, 1H), 4.05-4.12 (m, 1H), 0.79 (d, J=6.4 Hz, 3H).

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-bromo-5-(methylthio)benzyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-3-(5-amino-2-bromobenzyl)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(457 mg, 0.92 mmol) in methyl disulfide (4 mL) was added tert-butylnitrite (182 μL, d=0.867, 1.38 mmol). The resulting mixture was stirredat 80° C. for 1 h. An aliquot indicated completion of the reaction. Thetitled compound was obtained as a glassy material after preparative TLCplates eluted by 25% EtOAc in hexanes. LC-MS: 529.71 (M+1)⁺.

Example 342

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-chloro-4′-fluoro-5′-isopropyl-4-(methylthio)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-bromo-5-(methylthio)benzyl]-4-methyl-1,3-oxazolidin-2-one(60 mg, 0.114 mmol) in 1,4-dioxane (1 mL) was added(2-chloro-4-fluoro-5-isopropylphenyl)boronic acid (10 mg, 0.12 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (28 mg, 30mol %) and aqueous potassium hydroxide (95 μL, 3M, 2 eq.). The reactionmixture was purged with nitrogen and then sealed in a microwave vessel.The reaction vessel was subject to microwave irradiation at 150° C. for30 min. Crude mixture was worked up with water and EtOAc. The combinedorganic extracts were dried over Na₂SO₄ and concentrated in vacuo togive the crude product. This was purified by preparative TLC plate toafford the titled compound. LC-MS: 619.95 (M+1)⁺. ¹H NMR (CDCl₃, 500MHz) a 1:1 mixture of rotamers δ 7.83-7.88 (m, 1H), 7.72 (s, 1H) 7.68(s, 1H), 7.30-7.35 (m, 1H), 7.24-7.29 (m, 1H), 7.11-7.19 (m, 2.5H),7.04-7.07 (m, 0.5H), 5.62 (d, J=8.2 Hz, 0.5H), 5.24 (d, J=8.0 Hz, 0.5H),4.87 (d, J=15.3 Hz, 0.5H), 4.70 (d, J=15.8 Hz, 0.5H), 3.79-3.98 (m, 2H),3.18 (m, 1H), 2.55 (s, 1.5H), 2.54 (s, 1.5H), 1.20-1.29 (m, 6H), 0.53(d, J=6.4 Hz, 1.5H), 0.47 (d, J=−6.6 Hz, 1.5H).

Example 343

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(2′-chloro-5′-isopropyl-4-nitrobiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl-1,3-oxazolidin-2-one(950 mg, 1.80 mmol) in a toluene (5.2 mL): ethanol (2.6 mL): water (1.3mL) mixture was added (2-chloro-5-isopropylphenyl)boronic acid (325 mg,1.64 mmol), tetrakis(triphenylphosphine)palladium(0) (188 mg, 10 mol %)and sodium carbonate (346 mg, 3.26 mmol). The resulting mixture washeated in an 80° C. oil bath for 12 h. The reaction crude was evaporatedinto dryness. The resulting residue was taken up by a mixture of waterand EtOAc. The combined organic extracts were dried over Na₂SO₄ andconcentrated in vacuo to give the crude product, which was purified bySiO₂ (Biotage 40+S cartridge, EtOAc/hexane, gradient) to afford thetitled compound. LC-MS: 601.19 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) a 1:1mixture of rotamers δ 8.31-8.30 (m, 1H), 8.24-8.28 (m, 1H), 7.85-7.89(m, 1H), 7.68-7.76 (m, 2H), 7.42-7.48 (m, 2H), 7.26-7.30 (m, 1H),7.04-7.11 (m, 1H), 5.74 (d, J=7.8 Hz, 0.5H), 5.58 (d, J=8.0 Hz, 0.5H),4.92 (d, J=15.8 Hz, 0.5H), 4.76 (d, J=16.2 Hz, 0.5H), 3.97-4.04 (m,1.5H), 3.82 (dt, J=8.0, 6.6 Hz, 0.5H), 2.89-2.99 (m, 1H) 1.22-1.29 (m,6H), 0.60 (d, J=6.4 Hz, 1.5H), 0.52 (d, J=6.6 Hz, 1.5H).

Example 344

(4S,5R)-3-[(4-amino-2′-chloro-5′-isopropylbiphenyl-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

A solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(2′-chloro-5′-isopropyl-4-nitrobiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one(425 mg, 0.71 mmol) in methanol (10 mL) was subject to H₂ (40 psi., Parrshaker) at 20° C. for 6 h. The crude mixture was filtered through a bedof Celite (521). The filtrate was evaporated in vacuo to afford a glass.The titled compound was obtained after a preparative TLC plate developedby 20% EtOAc in hexanes. LC-MS: 571.22 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) a6:4 mixture of rotamers δ 7.82-7.86 (m, 1H), 7.65-7.71 (m, 2H),7.34-7.38 (m, 1H), 7.11-7.17 (m, 2H), 7.02-7.06 (m, 1H), 6.76-6.82 (m,1H), 6.68-6.74 (m, 1H), 5.58 (d, J=8.0 Hz, 0.4H), 5.51 (d, J=8.2 Hz,0.6H), 4.82 (d, J=15.3 Hz, 0.6H), 4.70 (d, J=15.6 Hz, 0.4H), 3.69-4.00(m, 4H), 2.84-2.94 (m, 1H), 1.19-1.28 (m, 6H), 0.45 (d, J=6.6 Hz, 1.2H),0.40 (d, J=6.6 Hz, 1.8H).

Example 345

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-2′-chloro-5′-isopropylbiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-3-[(4-amino-2′-chloro-5′-isopropylbiphenyl-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(100 mg, 0.175 mmol) in bromoform (0.5 mL) and dichloromethane (1 mL)was added t-butyl nitrite (23 μL, d=0.867, 90% pure, 0.193 mmol). Theresulting mixture was stirred at 50° C. for 1 h. An aliquot indicatedcompletion of the reaction. The reaction crude was deposited on 2prep-TLC plates eluted by dichloromethane to afford the title compound.LC-MS: 635.80 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) a 6:4 mixture of rotamersδ 7.84-7.88 (m, 1H), 7.67-7.74 (m, 2H), 7.60-7.63 (m, 1H), 7.51-7.57 (m,1H), 7.38-7.42 (m, 1H), 7.19-7.23 (m, 1H), 7.11-7.16 (m, 1H), 7.09 (d,J=2.3 Hz, 0.6H), 7.03 (d, J=2.3 Hz, 0.4H), 5.66 (d, J=8.0 Hz, 0.4H),5.55 (d, J=8.0 Hz, 0.6H), 4.86 (d, J=15.6 Hz, 0.6H), 4.70 (d, J=15.6 Hz,0.4H), 3.77-4.00 (m, 2H), 2.87-2.95 (m, 1H), 1.20-1.28 (m, 6H), 0.53 (d,J=6.6 Hz, 1.2H), 0.45 (d, J=6.4 Hz, 1.8H).

Example 346

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(2′-chloro-4-cyclopropyl-5′-isopropylbiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-2′-chloro-5′-isopropylbiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one(27 mg, 0.043 mmol) in 1,4-dioxane (1 mL) was added cyclopropylboronicacid (9 mg, 0.10 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (10.4 mg,30 mol %) and aqueous potassium hydroxide (42 μL, 3M, 3 eq.). Thereaction mixture was purged with nitrogen and then sealed in a microwavevessel. The reaction vessel was subject to microwave irradiation at 120°C. for 20 min. Crude mixture was worked up with water and EtOAc. Thecombined organic extracts were dried over Na₂SO₄ and concentrated invacuo to give the crude product. This was purified by preparative TLCplate eluted by 20% EtOAc in hexanes to afford the titled compound.LC-MS: 595.99 (M+1)⁺. ¹H NMR (CDCl₃, 500 MHz) a 6:4 mixture of rotamersδ 7.82-7.86 (m, 1H), 7.66-7.72 (m, 2H), 7.36-7.40 (m, 1H), 7.21-7.23 (m,0.5H), 7.11-7.19 (m, 3H), 7.01-7.08 (m, 1.5H), 5.58 (d, J=8.0 Hz, 0.4H),5.50 (d, J=8.0 Hz, 0.6H), 4.88 (d, J=15.1 Hz, 0.6H), 4.71 (d, J=15.6 Hz,0.4H), 3.76-3.95 (m, 2H), 2.84-2.95 (m, 1H), 1.92-2.00 (m, 1H),1.18-1.29 (m, 6H), 1.00-1.07 (m, 2H), 0.71-0.82 (m, 2H), 0.47 (d, J=6.6Hz, 1.2H), 0.42 (d, J=6.6 Hz, 1.8H).

Following the procedures outlined in EXAMPLE 96 the compounds listed inTable 18 were prepared from(4R,5R)-5-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)-biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one:

TABLE 18

LC/MS Data EXAMPLE R (M + 1) 347

570.3 348

538.4 349

511.4 350

532.4 351

508.4 352

562.4 353

643.5 354

570.4 355

586.4 356

503.4 357

503.4 358

618.5 359

518.4

Example 360

(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5′-isopropyl-2′-(trifluoromethoxy)-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one

To a solution of 80 mg of(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-onein 2 mL of benzene, 1 mL of water, and 0.5 mL ethanol was added 100 mgof 5-isopropyl-2-(trifluoromethoxy)phenyl boronic acid, 0.15 mL of 2Maqueous sodium carbonate, and 21 mg of Pd(PPh₃)₄. A reflux condenser wasattached, and the mixture was heated to 100° C. The mixture was stirredat 100° C. for 24 hours, and then was diluted with 10 mL of EtOAc and 10mL of water. The phases were separated and the aqueous phase wasextracted with 10 mL of EtOAc. The combined organic phases were washedwith 10 mL of brine, dried over Na₂SO₄, and concentrated. The residuewas purified by flash chromatography on a Biotage Horizon, 25M column,eluting with 1 CV of 2% EtOAc in hexanes, followed by a linear gradientof EtOAc in hexanes from 2 to 100% over 10 CV. The product wasrepurified using the same conditions to provide the title compound. Massspectrum (ESI) 674.4 (M+1).

Following the general procedures described above the compounds listed inTable 19 were prepared.

TABLE 19

LC/MS Data EXAMPLE A³ (M + 1) 361

580.3 362

642.4 363

614.3 364

616.3 365

634.4 366

650.3 367

674.4 368

623.9

(4R,5R)-4-ethyl-5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolidin-2-oneStep A: (4S)-4-benzyl-3-butyryl-1,3-oxazolidin-2-one

To a −78° C. solution of S-benzyl-oxazolidinone in 15 mL of THF wasadded n-BuLi over ca. 1 min, and then butyryl chloride. The mixture wasstirred for 30 min at −78° C., and then allowed to warm to r.t. over ca.30 min. Excess acid chloride was quenched by addition of 3 mL ofsaturated aqueous NH₄Cl, and then the bulk of the solvent was removed byrotary evaporation. The residue was diluted with 17 mL of saturatedaqueous NH₄Cl and 30 mL of CH₂Cl₂. The phases were separated and theaqueous phase was extracted with 20 mL of CH₂Cl₂. The combined organicextracts were washed with 20 mL of 1 N NaOH solution and 20 mL of brine,dried (Na₂SO₄), and concentrated. The residue was purified by flashchromatography on a Biotage Horizon, 40M column, eluting with 1 CV of 2%EtOAc in hexanes followed by a linear gradient of 2→100% EtOAc inhexanes over 10 CV. The residue was stored in the freezer overnight,where it crystallized. The resulting solid was triturated with hexanes,filtered, and dried under high vacuum. Mass spectrum (ESI) 178.2(M−C₃H₇CO).

Step B:(4S)-4-benzyl-3-((2R)-2-{(S)-hydroxy-[2-iodo-5-trifluoromethyl)phenyl]methyl}butanoyl)-1,3-oxazolidin-2-one

Following the procedure described in EXAMPLE 95, Step A, the titlecompound was prepared from5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde(EXAMPLE 80, Step A) and (4S)-4-benzyl-3-butyryl-1,3-oxazolidin-2-one.Mass spectrum (ESI) 530.1 (M−OH).

Step C:(4R,5R)-4-ethyl-5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one

Following the procedure described in EXAMPLE 95, Step B, the titlecompound was prepared from (4S)-4-benzyl-3-((2R)-2-{(S)-hydroxy[2-iodo-5-(trifluoromethyl)phenyl]methyl}butanoyl)-1,3-oxazolidin-2-one.Mass spectrum (ESI) 386.2 (M+1).

(4R,5R)-4-benzyl-5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolidin-2-oneStep A: (4S)-4-benzyl-3-(3-phenylpropanoyl)-1,3-oxazolidin-2-one

Following the procedure described in INTERMEDIATE 27, Step A, the titlecompound was prepared from S-benzyl-oxazolidinone and hydrocinnamoylchloride. Mass spectrum (ESI) 178.2 (M−PhC2H4CO).

Step B:(4S)-4-benzyl-3-{(2R,3S)-2-benzyl-3-hydroxy-3-[2-iodo-5-(trifluoromethyl)phenyl]propanoyl}-1,3-oxazolidin-2-one

Following the procedure described in EXAMPLE 95, Step A, the titlecompound was prepared from5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde(EXAMPLE 80, Step A) and(4S)-4-benzyl-3-(3-phenylpropanoyl)-1,3-oxazolidin-2-one. Mass spectrum(ESI) 592.3 (M−OH).

Step C:(4R,5R)-4-benzyl-5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one

Following the procedure described in EXAMPLE 95, Step B, the titlecompound was prepared from(4S)-4-benzyl-3-{(2R,3S)-2-benzyl-3-hydroxy-3-[2-iodo-5-(trifluoromethyl)phenyl]propanoyl}-1,3-oxazolidin-2-one.Mass spectrum (ESI) 448.2 (M+1).

Following the general procedures outlined above, the compounds in Table20 were prepared:

TABLE 20

LC/MS Data EXAMPLE A³ R₂ R₃ (M + 1) 369

Et

652.4 370

Et

584.4 371

Et

639.2

Example 372

Alternate procedure for making(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one(Example 73)

The compound of Example 73 can be made by the procedure shown below:

Step 1: Suzuki Coupling Reaction of Boronic Acid 1 and Aryl Chloride 2

A 3 M K₂CO₃ solution is prepared by adding 4.71 kg of solid K₂CO₃ to10.3 L water. Cooling is applied to keep the solution at 20-25° C. THF(12 L), aryl chloride 2 (2.69 kg), and the boronic acid 1 that was madein Example 78 (2.74 kg) are added to the K₂CO₃ followed by a 1 L THFrinse. HPLC analysis is used to confirm the 1.00/1.00 ratio of 1/2. Thesolution is degassed by sparging with nitrogen gas for 70 min. Thecatalyst, 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride(42 g) is added as a solid and is followed by a degassed THF rinse (1.5L). The organic layer turns dark brown immediately. The biphasic mixtureis aged at 36°-40° C. with vigorous stirring. After HPLC revealscomplete conversion (15-18 h), the mixture is cooled to rt and theaqueous layer is removed. To the organic layer is added heptane (25.6 L)and water (25.6 L) and the layers are cut. The organic layer is washedwith water (19 L). The organic layer is treated with 680 g Darco KB-B atrt for 60 min and filtered through solka-floc with a 10% THF/Heptanerinse (˜15 L). The solvent is switched to heptane (˜35 L) at ˜45-50° C.until <0.5 v % of THF is left. More heptane is added to bring the totalvolume to ˜45-50 L. The solution is seeded with crystals obtained fromearlier runs if no seed bed forms. The slurry is slowly cooled to rt andthen to −15° C. After aging at −15° C. for 1-2 h, after LC of thesupernatant shows ˜2 g/l loss of the product in the supernatant, theslurry is filtered and the product is washed with cold heptane (˜25 L),providing compound 3.

Step 2: Chlorination of 3 to 4

To a solution of biaryl 3 (3.4 kg) in DMF (17 L) which was maintained at10° C. was added thionyl chloride (940 ml), and then the mixture waswarmed to room temperature. The mixture was aged until >99.8% conversionwas measured by HPLC. Water (3.4 L) was then added. Seed crystals (1 wt%) were added, and the mixture was aged for 30 min more before slowlyadding 5.1 L of additional water over ˜1 hr. The solid was filtered andwashed with first 20 L 1:1 DMF: water and then 3×20 L water. The solidproduct 4 was dried at 20° C. until <0.1 wt % water remained.

Step 3: Alkylation of the Product of Example 17 with Compound 4 to Yieldthe Product of Example 73

The chiral intermediate(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-onewhich was made in Example 17 is dissolved in DMF (2.8 kg in 32.7 L) andcooled to −15° C. 2.0 M NaHMDS (3.92 L, 1.05 eq) was then added over 1.5hr, followed by addition of the biaryl chloride 4 (2.8 kg) in DMF. Themixture was warmed to +12° C. and was aged until complete conversiontook place. Then 5N HCl (3.4 L) was added, followed by 16 L of 10%IPAC/Heptane and 34 L of water, keeping the temperature between 10° C.and 20° C. throughout. The layers were cut and the organic layer waswashed twice with 14 L of 1:1 DMF:water followed by two 14 L waterwashes. The organic layer was assayed for yield and was then filteredthrough 2.4 kg of silica gel to remove the excess oxazolidinone to<0.5%. The silica was washed with 5% IPAC/Heptane. The combined organicsolutions were distilled to remove IPAC to <1%. The warm heptanesolution was then transferred slowly into a 20° C. heptane solutioncontaining 10 wt % seed. The slurry was then cooled to −20° C. andfiltered. The filter cake was washed with cold heptane and was thendried, yielding the compound that was originally made in Example 73.

(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-3-nitro-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

(4R,5R)-3-[3,5-Bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-onewas added in portions to 2 mL of fuming nitric acid at 0° C. Thereaction mixture was stirred overnight at r.t., and then heated to 75°C. for 4 h. The reaction mixture was cooled and then added dropwise to arapidly stirred mixture of 10 mL of water and 10 mL of EtOAc. The phaseswere separated and the organic phase was washed with 10 mL each ofsaturated NaHCO₃ and brine, dried (Na₂SO₄), and concentrated. Theresidue was purified by flash chromatography on a Biotage Horizon, 25Scolumn, eluting with 1 CV of 5% EtOAc in hexanes followed by a lineargradient of 5→100% EtOAc in hexanes over 10 CV, to provide the titlecompound. Mass spectrum (ESI) 643 (M+1).

Example 373

(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[4′-fluoro-5′-isopropyl-2′-methoxy-6-nitro-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one

Following the procedure described in EXAMPLE 81, 48 mg of(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-3-nitro-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-oneand 48 mg of (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (EXAMPLE78) provided two atroposiomers, which were separable by flashchromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 5%EtOAc in hexanes followed by a linear gradient of 5→100% EtOAc inhexanes over 10 CV, providing atropoisomer A [mass spectrum (ESI) 683.4(M+1)] and atropoisomer B [mass spectrum (ESI) 683.3 (M+1)].

Example 374

(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[4′-fluoro-5′-isopropyl-2′-methoxy-6-iodo-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one(atropoisomer A)

To a solution of 17 mg of(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[4′-fluoro-5′-isopropyl-2′-methoxy-6-nitro-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one,atropoisomer A (EXAMPLE 373), in 1 mL EtOAc was added 5 mg of PtO₂(Adam's catalyst). The reaction mixture was flushed with H₂, and thenstirred under an H₂ balloon for 2 h, at which point LC/MS analysisshowed mostly the nitroso product. The reaction mixture was filteredthrough Celite, washing liberally with EtOAc, and the filtrate wasconcentrated and resubmitted to reaction conditions overnight. Thereaction mixture was filtered through Celite, washing liberally withEtOAc, and the filtrate was concentrated. The residue was dissolved in0.5 mL of CH₂I₂ and 6 μL of t-butyl nitrite was added. The reactionmixture was stirred for 1.5 h at 80° C. The reaction mixture waspurified by preparative thin-layer chromatography on a 1000 μM plate,eluting with 20% EtOAc in hexanes, to provide the title compound. Massspectrum (ESI) 764.3 (M+1).

Example 375

(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[4′-fluoro-5′-isopropyl-2′-methoxy-6-iodo-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one(atropoisomer B)

To a solution of 70 mg of(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-3-nitro-4-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one(intermediate 30) in 1 mL EtOH was added 124 mg of SnCl₂. The reactionmixture was stirred overnight at r.t; then another 60 mg of SnCl₂ wasadded and the mixture was heated to 80° C. and stirred overnight. Thereaction mixture was concentrated and the residue was partitionedbetween 10 mL of CH₂Cl₂ and 10 mL of 1 N NaOH. The aqueous phase wasextracted with 2×10 mL of CH₂Cl₂ and the combined organics were dried(Na₂SO₄), and concentrated. Following the procedure described in EXAMPLE81, the residue from the reduction and 70 mg of(4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (EXAMPLE 78) providedthe corresponding biphenyl compound as a mixture of atropoisomers. Thismixture was dissolved in 0.5 mL of CH₂I₂ and 14 μL of t-butyl nitritewas added. The reaction mixture was stirred for 1.5 h at 80° C. and thencooled and added directly to two 1000-μM thin-layer chromatographyplates, eluting with 20% EtOAc in hexanes to provide approximately equalamounts of atropoisomer A and B of the title compound. Mass spectrum(ESI) 764.2 (M+1).

4′-fluoro-5-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde

Following the procedure described in EXAMPLE 81, 200 mg of2-iodo-5-(trifluoromethyl)benzaldehyde (EXAMPLE 80, Step A) and 170 mgof (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (EXAMPLE 78) gavethe title compound. Mass spectrum (ESI) 341.3 (M+1).

5-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1-(4-methoxybenzyl)imidazolidin-2-oneStep A:[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl][(4-methoxybenzyl)amino]acetonitrile

To a solution of 203 mg of4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde(INTERMEDIATE 31) in 2 mL of CH₂Cl₂ was added 100 μL of TMSCN, and then1 mg of ZnI₂. The mixture was stirred for 30 min at r.t.p-Methoxybenzylamine (157 μL) in 2 mL of MeOH was added and the mixturewas heated to reflux for 1.5 h. The reaction mixture was cooled andconcentrated. The residue was purified by flash chromatography on aBiotage Horizon, 25M column, eluting with 1 CV of 2% EtOAc in hexanesfollowed by a linear gradient of 2→100% EtOAc in hexanes over 10 CV toprovide the title compound. Mass spectrum (ESI) 487.2 (M+1).

Step B:5-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1-(4-methoxybenzyl)imidazolidin-2-one

To a 0° C. solution of 100 mg of[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl][(4-methoxybenzyl)amino]acetonitrilein 4 mL of THF was added 620 μL of a 1 M solution of LiAlH₄ in Et₂O. Thecooling bath was removed and the mixture was stirred for 45 min at r.t.The mixture was recooled to 0° C. and carefully quenched by dropwiseaddition of 24 μL of water, 24 μL of 15% aqueous NaOH solution, and 60μL of water. The solids were filtered, washing liberally with Et₂O, andthe filtrate was concentrated. The residue was dissolved in 2 mL ofCH₂Cl₂ and cooled to 0° C. Triethylamine (55 μL) and then triphosgene(32 mg) were added. The mixture was stirred for 45 min at 0° C. Thereaction mixture was partitioned between 10 mL of EtOAc and 10 mL ofwater. The aqueous was extracted with 10 mL of EtOAc and the combinedorganics were washed with 10 mL of brine, dried (Na₂SO₄), andconcentrated. The residue was purified by flash chromatography on aBiotage Horizon, 25S column, eluting with 1 CV of 15% EtOAc in hexanesfollowed by a linear gradient of 15→100% EtOAc in hexanes over 10 CV toprovide the title compound. Mass spectrum (ESI) 517.3 (M+1).

Example 376

1-[3,5-bis(trifluoromethyl)benzyl]-4-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]imidazolidin-2-oneStep A:1-[3,5-bis(rifluoromethyl)benzyl]-4-[4′-fluoro-5-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-3-(4-methoxybenzyl)imidazolidin-2-one

To a 0° C. solution of 19 mg of5-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1-(4-methoxybenzyl)imidazolidin-2-one(INTERMEDIATE 32) in 1 mL of DMF was added 3 mg of NaH (60% dispersionin oil). The solution was stirred for 10 min at 0° C. and then 8 μL of3,5-bistrifluoromethylbenzyl bromide was added and the mixture wasstirred for 3 h at 0° C. The reaction mixture was quenched with a dropof water and then filtered and purified by reverse-phase HPLC [WatersXTerra C8 19×50 mm column, eluting at 20 mL/min with 90% water (0.1%TFA) to 100% acetonitrile (0.1% TFA) over 5.15 min, hold for 1.45 min,then back to 90% water over 0.5 min] to provide the title compound. Massspectrum (ESI) 743.2 (M+1).

Step B:1-[3,5-bis(trifluoromethyl)benzyl]-4-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]imidazolidin-2-one

A solution of 15 mg of1-[3,5-bis(trifluoromethyl)benzyl]-4-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-3-(4-methoxybenzyl)imidazolidin-2-onein 0.5 mL of TFA was stirred overnight at r.t. The reaction mixture wasconcentrated and then purified by reverse-phase HPLC [Waters XTerra C819×25 mm column, eluting at 20 mL/min with 90% water (0.1% TFA) to 100%acetonitrile (0.1% TFA) over 5.15 min, hold for 1.45 min, then back to90% water over 0.5 min] to provide the title compound. Mass spectrum(ESI) 623.4 (M+1).

Example 377

1-benzyl-4-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]imidazolidin-2-oneStep A:1-benzyl-4-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-3-(4-methoxybenzyl)imidazolidin-2-one

Following the procedure described in EXAMPLE 379, Step A, 31 mg of5-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1-(4-methoxybenzyl)imidazolidin-2-one(INTERMEDIATE 32) and 9 μL of benzyl bromide gave the title compound.Mass spectrum (ESI) 607.5 (M+1).

Step B:1-benzyl-4-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]imidazolidin-2-one

Following the procedure described in EXAMPLE 379, Step B, 5 mg of1-benzyl-4-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-3-(4-methoxybenzyl)imidazolidin-2-onegave the title compound. Mass spectrum (ESI) 487.4 (M+1).

1. A compound having Formula I, or a pharmaceutically acceptable saltthereof, wherein

Y is selected from the group consisting of —C(═O)— and —(CRR¹)—; X isselected from the group consisting of —O—, —NH—, —N(C₁-C₅alkyl)-, and—(CRR⁶)—; Z is selected from the group consisting of —C(═O)—, —S(O)₂—,and —C(═N—R⁹)—, wherein R⁹ is selected from the group consisting of H,—CN, and C₁-C₅alkyl optionally substituted with 1-11 halogens; Each R isindependently selected from the group consisting of H, —C₁-C₅ alkyl, andhalogen, wherein —C₁-C₅ alkyl is optionally substituted with 1-11halogens; B is selected from the group consisting of A¹ and A², whereinA¹ has the structure:

R¹ and R⁶ are each selected from the group consisting of H, —C₁-C₅alkyl, halogen, and —(C(R)₂)_(n)A², wherein —C₁-C₅ alkyl is optionallysubstituted with 1-11 halogens; R² is selected from the group consistingof H, —C₁-C₅ alkyl, halogen, A¹, and —(C(R)₂)_(n)A², wherein —C₁-C₅alkyl is optionally substituted with 1-11 halogens; Wherein one of B andR² is A¹; and one of B, R¹, R², and R⁶ is A² or (C(R)₂)_(n)A²; so thatthe compound of Formula I comprises one group A¹ and one group A²; A³ isselected from the group consisting of: (a) an aromatic ring selectedfrom phenyl and naphthyl; (b) a phenyl ring fused to a 5-7 memberednon-aromatic cycloalkyl ring, which optionally comprises 1-2 doublebonds; (c) a 5-6-membered heterocyclic ring having 1-4 heteroatomsindependently selected from N, S, O, and —N(O)—, and optionally alsocomprising 1-3 double bonds and a carbonyl group, wherein the point ofattachment of A³ to the phenyl ring to which A³ is attached is a carbonatom; and (d) a benzoheterocyclic ring comprising a phenyl ring fused toa 5-6-membered heterocyclic ring having 1-2 heteroatoms independentlyselected from O, N, and —S(O)_(x)— and optionally 1-2 double bonds,wherein the point of attachment of A³ to the phenyl ring to which A³ isattached is a carbon atom; A² is selected from the group consisting of:(a) an aromatic ring selected from phenyl and naphthyl; (b) a phenylring fused to a 5-7 membered non-aromatic cycloalkyl ring, whichoptionally comprises 1-2 double bonds; (c) a 5-6-membered heterocyclicring having 1-4 heteroatoms independently selected from N, S, O, and—N(O)—, and optionally also comprising 1-3 double bonds and a carbonylgroup; (d) a benzoheterocyclic ring comprising a phenyl ring fused to a5-6-membered heterocyclic ring having 1-2 heteroatoms independentlyselected from O, N, and S and optionally 1-2 double bonds; and (e) a—C₃-C₈ cycloalkyl ring optionally having 1-3 double bonds; wherein A³and A² are each optionally substituted with 1-5 substituent groupsindependently selected from R^(a); Each R^(a) is independently selectedfrom the group consisting of —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, —C₃-C₈ cycloalkyl optionally having 1-3 double bonds,—OC₁-C₆alkyl, —OC₂-C₆ alkenyl, —OC₂-C₆ alkynyl, —OC₃-C₈ cycloalkyloptionally having 1-3 double bonds, —C(═O)C₁-C₆alkyl, —C(═O)C₃-C₈cycloalkyl, —C(═O)H, —CO₂H, —CO₂C₁-C₆alkyl, —C(═O)SC₁-C₆alkyl, —OH,—NR³R⁴, —C(═O)NR³R⁴, —NR³C(═O)OC₁-C₆ alkyl, —NR³C(═O)NR³R⁴,—S(O)_(x)C₁-C₆ alkyl, —S(O)_(y)NR³R⁴, —NR³S(O)_(y)NR³R⁴, halogen, —CN,—NO₂, and a 5-6-membered heterocyclic ring having 1-4 heteroatomsindependently selected from N, S, and O, said heterocyclic ringoptionally also comprising a carbonyl group and optionally alsocomprising 1-3 double bonds, wherein the point of attachment of saidheterocyclic ring to the ring to which R^(a) is attached is a carbonatom, wherein said heterocyclic ring is optionally substituted with 1-5substituent groups independently selected from halogen, —C₁-C₃ alkyl,and —OC₁-C₃ alkyl, wherein —C₁-C₃ alkyl and —OC₁-C₃ alkyl are optionallysubstituted with 1-7 halogens; wherein for compounds in which R^(a) isselected from the group consisting of —C₁-C₆ alkyl, —C₂-C₆ alkenyl,—C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl optionally having 1-3 double bonds,—OC₁-C₆alkyl, —OC₂-C₆ alkenyl, —OC₂-C₆ alkynyl, —OC₃-C₈ cycloalkyloptionally having 1-3 double bonds, —C(═O)C₁-C₆alkyl, —C(═O)C₃-C₈cycloalkyl, —CO₂C₁-C₆alkyl, —C(═O)SC₁-C₆alkyl, —NR³C(═O)OC₁-C₆ alkyl,and —S(O)_(x)C₁-C₆ alkyl, then R^(a) is optionally substituted with 1-15halogens and is optionally also substituted with 1-3 substituent groupsindependently selected from (a) —OH, (b) —CN, (c) —NR³R⁴, (d) —C₃-C₈cycloalkyl optionally having 1-3 double bonds and optionally substitutedwith 1-15 halogens, (e) —OC₁-C₄alkyl optionally substituted with 1-9halogens and optionally also substituted with 1-2 substituent groupsindependently selected from —OC₁-C₂ alkyl and phenyl, (f) —OC₃-C₈cycloalkyl optionally having 1-3 double bonds and optionally substitutedwith 1-15 halogens, (g) —CO₂H, (h) —C(═O)CH₃, (i) —CO₂C₁-C₄alkyl whichis optionally substituted with 1-9 halogens, and (j) phenyl which isoptionally substituted with 1-3 groups independently selected fromhalogen, —CH₃, —CF₃, —OCH₃, and —OCF₃; with the proviso that when B isA¹, and X and Y are —CH₂—, and Z is —C(═O)—, and R² is phenyl which hasa substituent R^(a) in the 4-position, wherein R^(a) is —OC₁-C₆alkylwhich is optionally substituted as described above, then there are noother R^(a) substitutents on R² in which R^(a) is selected from —OH,—OC₁-C₆alkyl, —OC₂-C₆ alkenyl, —OC₂-C₆ alkynyl, and —OC₃-C₈ cycloalkyloptionally having 1-3 double bonds, optionally substituted as describedabove. n is 0 or 1; p is an integer from 0-4; x is 0, 1, or 2; y is 1 or2; R³ and R⁴ are each independently selected from H, —C₁-C₅ alkyl,—C(═O)C₁-C₅ alkyl and —S(O)_(y)C₁-C₅ alkyl, wherein —C₁-C₅ alkyl in allinstances is optionally substituted with 1-11 halogens; and R⁵ isselected from the group consisting of H, —OH, —C₁-C₅ alkyl, and halogen,wherein —C₁-C₅ alkyl is optionally substituted with 1-11 halogens. 2.The compound of claim 1, which is selected from the group consisting ofcompounds having Formula Ia, Ib, and Id, or a pharmaceuticallyacceptable salt thereof:


3. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein: Y is —(CRR¹)—; R and R⁶ are each independentlyselected from the group consisting of H and —C₁-C₅ alkyl, wherein —C₁-C₅alkyl is optionally substituted with 1-11 halogens; R¹ is selected fromthe group consisting of H, —C₁-C₅ alkyl, and —(C(R)₂)_(n)A², wherein—C₁-C₅ alkyl is optionally substituted with 1-11 halogens; Wherein oneof B and R² is A¹; and one of B, R¹, and R² is A² or —(C(R)₂)_(n)A²; sothat the compound of Formula I comprises one group A¹ and one group A²;A³ is selected from the group consisting of: (a) an aromatic ringselected from phenyl and naphthyl; (b) a 5-6-membered heterocyclic ringhaving 1-4 heteroatoms independently selected from N, S, O, and —N(O)—,and optionally also comprising 1-3 double bonds and a carbonyl group,wherein the point of attachment of A³ to the phenyl ring to which A³ isattached is a carbon atom; and (c) a benzoheterocyclic ring comprising aphenyl ring fused to a 5-6-membered heterocyclic ring having 1-2heteroatoms independently selected from O, N, and —S(O)_(x)— andoptionally 1-2 double bonds, wherein the point of attachment of A³ tothe phenyl ring to which A³ is attached is a carbon atom; A² is selectedfrom the group consisting of: (a) an aromatic ring selected from phenyland naphthyl; (b) a 5-6-membered heterocyclic ring having 1-4heteroatoms independently selected from N, S, O, and —N(O)—, andoptionally also comprising 1-3 double bonds and a carbonyl group; (c) abenzoheterocyclic ring comprising a phenyl ring fused to a 5-6-memberedheterocyclic ring having 1-2 heteroatoms independently selected from O,N, and S and optionally 1-2 double bonds; and (d) a —C₃-C₈ cycloalkylring optionally having 1-3 double bonds; wherein A³ and A² are eachoptionally substituted with 1-4 substituent groups independentlyselected from R^(a); Each R^(a) is independently selected from the groupconsisting of —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₃-C₈ cycloalkyl optionallyhaving 1-3 double bonds, —OC₁-C₆alkyl, —C(═O)H, —CO₂H, —CO₂C₁-C₆alkyl,—OH, —NR³R⁴, —NR³C(═O)OC₁-C₆ alkyl, —S(O)_(x)C₁-C₆ alkyl, halogen, —CN,—NO₂, and a 5-6-membered heterocyclic ring having 1-4 heteroatomsindependently selected from N, S, and O, said heterocyclic ringoptionally also comprising a carbonyl group and optionally alsocomprising 1-3 double bonds, wherein the point of attachment of saidheterocyclic ring to the ring to which R^(a) is attached is a carbonatom, wherein said heterocyclic ring is optionally substituted with 1-5substituent groups independently selected from halogen, —C₁-C₃ alkyl,and —OC₁-C₃ alkyl, wherein —C₁-C₃ alkyl and —OC₁-C₃ alkyl are optionallysubstituted with 1-7 halogens; wherein for compounds in which R^(a) isselected from the group consisting of —C₁-C₆ alkyl, —C₂-C₆ alkenyl,—C₃-C₈ cycloalkyl optionally having 1-3 double bonds, —OC₁-C₆alkyl,—C(═O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl, —NR³C(═O)OC₁-C₆ alkyl, and—S(O)_(x)C₁-C₆ alkyl, R^(a) is optionally substituted with 1-15 halogensand is optionally also substituted with one substituent group selectedfrom (a) —OH, (b) —NR³R⁴, (c) —OC₁-C₄alkyl optionally substituted with1-9 halogens and optionally also substituted with 1-2 substituent groupsindependently selected from —OC₁-C₂ alkyl and phenyl, and (d) phenylwhich is optionally substituted with 1-3 groups independently selectedfrom halogen, —CH₃, —CF₃, —OCH₃, and —OCF₃; with the proviso that when Bis A¹, and X and Y are —CH₂—, and Z is —C(═O)—, and R² is phenyl whichhas a substituent R^(a) in the 4-position, wherein R^(a) is —OC₁-C₆alkylwhich is optionally substituted as described above, then there are noother R^(a) substitutents on R² in which R^(a) is —OH or —OC₁-C₆alkylwhich is optionally substituted as described above; p is an integer from0-2; R³ and R⁴ are each independently selected from H and —C₁-C₅ alkyl,wherein —C₁-C₅ alkyl in all instances is optionally substituted with1-11 halogens; and R⁵ is selected from the group consisting of H, —OH,and —C₁-C₅ alkyl, wherein —C₁-C₅ alkyl is optionally substituted with1-11 halogens.
 4. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein: Y is —(CRR¹)—; Z is selected from thegroup consisting of —C(═O)—, —S(O)₂—, and —C(═N—R⁹)—, wherein R⁹ isselected from the group consisting of H, —CN, and CH₃; Each R isindependently selected from the group consisting of H and C₁-C₂ alkyl;R⁶ is selected from the group consisting of H and —C₁-C₃ alkyl, whereinC₁-C₃ alkyl is optionally substituted with 1-5 halogens; R¹ is selectedfrom the group consisting of H, —C₁-C₃ alkyl, and —(C(R)₂)_(n)A²,wherein —C₁-C₃ alkyl is optionally substituted with 1-5 halogens; R² isselected from the group consisting of H, —C₁-C₃ alkyl, A¹, and—(C(R)₂)_(n)A², wherein —C₁-C₃ alkyl is optionally substituted with 1-5halogens; Wherein one of B and R² is A¹; and one of B, R¹, and R² is A²or —(C(R)₂)_(n)A²; so that the compound of Formula I comprises one groupA¹ and one group A²; A³ is selected from the group consisting of: (a)phenyl; (b) a 5-6-membered aromatic heterocyclic ring having 1-2heteroatoms independently selected from N, S, O, and —N(O)—, wherein thepoint of attachment of A³ to the phenyl ring to which A³ is attached isa carbon atom; and (c) a benzoheterocyclic ring comprising a phenyl ringfused to a 5-membered aromatic heterocyclic ring having 1-2 heteroatomsindependently selected from O, N, and —S(O)_(x), wherein the point ofattachment of A³ to the phenyl ring to which A³ is attached is a carbonatom; A² is selected from the group consisting of: (a) phenyl; (b) a5-6-membered heterocyclic ring having 1-4 heteroatoms independentlyselected from N, S, O, and —N(O)—, and optionally also comprising 1-3double bonds; (c) a benzoheterocyclic ring comprising a phenyl ringfused to a 5-membered heterocyclic ring having 1-2 heteroatomsindependently selected from O, N, and S; and (d) a —C₅-C₆ cycloalkylring; wherein A³ and A² are each optionally substituted with 1-4substituent groups independently selected from R^(a); Each R^(a) isindependently selected from the group consisting of —C₁-C₄ alkyl, —C₂-C₄alkenyl, cyclopropyl, —OC₁-C₂alkyl, —C(═O)H, —CO₂C₁-C₄alkyl, —OH,—NR³R⁴, —NR³C(═O)OC₁-C₄ alkyl, —S(O)_(x)C₁-C₂ alkyl, halogen, —CN, —NO₂,and a 5-6-membered heterocyclic ring having 1-2 heteroatomsindependently selected from N, S, and O, wherein the point of attachmentof said heterocyclic ring to the ring to which R^(a) is attached ring isa carbon atom, wherein said heterocyclic ring is optionally substitutedwith 1-5 substituent groups independently selected from halogen; whereinfor compounds in which R^(a) is selected from the group consisting of—C₁-C₄ alkyl, —C₂-C₄ alkenyl, —OC₁-C₂alkyl, —C(═O)C₁-C₂alkyl,—CO₂C₁-C₄alkyl, —NR³C(═O)OC₁-C₄ alkyl, and —S(O)_(x)C₁-C₂ alkyl, thealkyl group of R^(a) is optionally substituted with 1-5 halogens and isoptionally also substituted with one substituent group selected from (a)—OH, (b) —NR³R⁴, (c) —OCH₃ optionally substituted with 1-3 fluorineatoms and optionally also substituted with one phenyl group, and (d)phenyl which is optionally substituted with 1-3 groups independentlyselected from halogen, —CH₃, —CF₃, —OCH₃, and —OCF₃; with the provisothat when B is A¹, and X and Y are —CH₂—, and Z is —C(═O)—, and R² isphenyl which has a substituent R^(a) in the 4-position, wherein R^(a) is—OC₁-C₂alkyl which is optionally substituted as described above, thenthere are no other R^(a) substitutents on R² in which R^(a) is selectedfrom —OH or —OC₁-C₂alkyl which is optionally substituted as describedabove; p is an integer from 0-2; and R³, R⁴, and R⁵ are eachindependently selected from H and —C₁-C₃ alkyl.
 5. The compound of claim4, or a pharmaceutically acceptable salt thereof, wherein A³ is selectedfrom the group consisting of phenyl, thienyl, imidazolyl, pyrrolyl,pyrazolyl, pyridyl, N-oxido-pyridyl, thiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, benzothienyl, benzothienyl-5-oxide, andbenzothienyl-5-dioxide; and A² is selected from the group consisting ofphenyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, pyrazolyl,1,2,4-triazolyl, tetrazolyl, benzodioxolyl, pyridyl, N-oxido-pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, cyclopentyl, cyclohexyl, andtetrahydropyranyl.
 6. The compound of claim 5, or a pharmaceuticallyacceptable salt thereof, wherein X is selected from the group consistingof —O—, —NH—, and —N(C₁-C₃alkyl)-; and Z is —C(═O)—.
 7. The compound ofclaim 4, or a pharmaceutically acceptable salt thereof, wherein A² andA³ are both phenyl; and R^(a) is selected from the group consisting of—C₁-C₄ alkyl which is optionally substituted with 1-5 fluorine atoms andis optionally also substituted with one group selected from —OH and—OCH₃; —OC₁-C₂alkyl, which is optionally substituted with 1-3 fluorineatoms; —C₂-C₄ alkenyl; —C₁-C₂ alkyl which is substituted with one group—NR³R⁴; —C₁-C₂ alkyl-O—C₁-C₂ alkyl-phenyl; cyclopropyl; —C(═O)H; —OH;—NR³R⁴; —S(O)_(x)C₁-C₂ alkyl; halogen; —CN; —NO₂; and a 5-6-memberedheterocyclic ring comprising 1-2 oxygen atoms which is optionallysubstituted with C₁-C₂alkyl; subject to the same proviso as in claim 4.8. The compound of claim 7 having Formula Ii, or a pharmaceuticallyacceptable salt thereof, wherein:

R⁷ is selected from the group consisting of Cl and —CF₃; Each R^(b) isindependently selected from the group consisting of —C₁-C₃ alkyl, —OCH₃,and F; R¹ is selected from the group consisting of H and —C₁-C₂ alkyl;R^(c) is selected from the group consisting of halogen, —CH₃—CF₃, and—CN; q is 2 or 3; and t is an integer from 0-2.
 9. The compound of claim7 having Formula Ij, or a pharmaceutically acceptable acceptable saltthereof, wherein:

R⁷ is selected from the group consisting of Cl and —CF₃; Each R^(b) isindependently selected from the group consisting of —C₁-C₃ alkyl, —OCH₃,and F; R¹ is selected from the group consisting of H and —C₁-C₂ alkyl;R^(c) is selected from the group consisting of halogen, —CH₃—CF₃, and—CN; q is 2 or 3; and t is an integer from 0-2.
 10. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein A³ isphenyl, which is optionally substituted with 1-4 substituent groupsR^(a), wherein R^(a) is independently selected from —C₁-C₅ alkyl,—OC₁-C₃alkyl, —CO₂C₁-C₃alkyl, —CO₂H, halogen, —NR³R⁴, —C(═O)C₁-C₃alkyl,—C(═O)H, —C(═O)NR³R⁴, —SC₁-C₃ alkyl, —C₂-C₃ alkenyl, —CN, —NO₂, and1,2,4-oxadiazolyl, wherein —C₁-C₃ alkyl and —C₁-C₅ alkyl in alloccurrences is optionally substituted with 1-6 substituentsindependently selected from 1-5 halogens and one —OH group; and —C₂-C₃alkenyl is optionally substituted with 1-3 halogens; A² is selected fromthe group consisting of phenyl, cyclohexyl, and a heterocyclic 5-6membered ring comprising 1-2 heteroatoms independently selected from O,N, S, and —N(O)— and optionally also comprising 1-3 double bonds,wherein A² is optionally substituted with 1-2 substituent groupsindependently selected from —C₁-C₄ alkyl, —OC₁-C₃ alkyl, —NO₂, —CN,—S(O)_(x)C₁-C₃ alkyl, —NHS(O)₂C₁-C₃ alkyl, —NR³R⁴, —NR³C(═O)R⁴, —C₂-C₃alkenyl, —C(═O)NR³R⁴, halogen, and pyridyl, wherein C₁-C₃ alkyl, C₁-C₄alkyl, and C₂-C₃alkenyl in all instances is optionally substituted with1-3 halogens, with the proviso that when B is A¹, and X and Y are —CH₂—,and Z is —C(═O)—, and R² is phenyl which has a substituent R^(a) in the4-position in which R^(a) is —OC₁-C₃alkyl which is optionallysubstituted as described above, then there are no other R^(a)substitutents on R² in which R^(a) is —OC₁-C₃alkyl optionallysubstituted as described above; R³ and R⁴ are each independentlyselected from H and —C₁-C₃ alkyl; and p is 0-2.
 11. The compound ofclaim 10, or a pharmaceutically acceptable salt thereof, wherein A¹ is

R⁷ and R⁸ are each independently selected from the group consisting ofH, halogen, —NR³R⁴, —C₁-C₃ alkyl, —OC₁-C₃ alkyl, —CN, —NO₂, and pyridyl,wherein C₁-C₃ alkyl in all instances is optionally substituted with 1-3halogens; and A² is selected from the group consisting of phenyl,pyridyl, and cyclohexyl, wherein A² is optionally substituted with 1-2substituents independently selected from —C₁-C₄ alkyl, —OC₁-C₃ alkyl,—NO₂, —CN, and halogen, wherein C₁-C₄ alkyl and C₁-C₃ alkyl in all usesis optionally substituted with 1-3 halogens, with the proviso that whenB is A¹, and X and Y are —CH₂—, and Z is —C(═O)—, and R² is phenyl whichhas a substituent R^(a) in the 4-position, wherein R^(a) is —OC₁-C₃alkylwhich is optionally substituted with 1-3 halogens, then there are noother R^(a) substitutents on R² in which R^(a) is selected from—OC₁-C₃alkyl which is optionally substituted with 1-3 halogens.
 12. Thecompound of claim 11, or a pharmaceutically acceptable salt thereof,wherein A¹ is

R⁷ is selected from the group consisting of H, halogen, —NR³R⁴, —C₁-C₃alkyl, —OC₁-C₃ alkyl, —CN, —NO₂, and pyridyl, wherein C₁-C₃ alkyl in allinstances is optionally substituted with 1-3 halogens; and R⁸ isselected from the group consisting of H, halogen, —CH₃, —CF₃, —OCH₃, and—OCF₃.
 13. A pharmaceutical composition comprising the compound of claim1, or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 14. The compound of claim 4, which is selected fromthe group consisting of the following compounds, or a pharmaceuticallyacceptable salt thereof:


15. The compound of claim 4, which is selected from the group consistingof compounds with the formula (a) to (c), or a pharmaceuticallyacceptable salt thereof:

wherein R is selected from the group consisting of

wherein R is selected from the group consisting of

wherein R is selected from the group consisting of


16. The compound of claim 4, which is selected from the group consistingof the following compounds, or a pharmaceutically acceptable saltthereof:


17. The compound of claim 4, selected from the group consisting ofcompounds having the formula (a) to (k), or a pharmaceuticallyacceptable salt thereof:

wherein A³, A², and Z for the compounds (1) to (6) are selected from thegroup consisting of: A³ A² Z (1)

CO (2)

CO (3)

CO (4)

CO (5)

CO and (6)

SO₂;

wherein A³ is selected from the group consisting of:

wherein A3 and A2 for the compounds (1) to (6) are selected from thegroup consisting of: A³ A² (1)

(2)

(3)

(4)

(5)

(6)

wherein R is selected from the group consisting of

wherein R is Et or n-Pr;

wherein R and A3 for the compounds (1) to (4) are selected from thegroup consisting of R A³ (1)

(2)

(3)

(4)

wherein R is selected from the group consisting of:

wherein A² is selected from the group consisting of

wherein R is selected from the group consisting of

wherein A³ is selected from the group consisting of:

wherein A³, R₂ and R₃ for the compounds (1) to (3) are selected from thegroup consisting of: A³ R₂ R₃ (1)

Et

(2)

Et

(3)

Et


18. A method of treating atherosclerosis in a patient in need oftreatment comprising the administration of a therapeutically effectiveamount of the compound of claim 1 to said patient, or a pharmaceuticallyacceptable salt thereof.
 19. A method of raising HDL-C in a patient inneed of treatment comprising the administration of a therapeuticallyeffective amount of the compound of claim 1 to said patient, or apharmaceutically acceptable salt thereof.
 20. The use of the compound ofclaim 1 or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for the treatment of atherosclerosis.
 21. Apharmaceutical composition comprising the compound of claim 1 or apharmaceutically acceptable salt thereof, a pharmaceutically acceptablecarrier, and one or more active ingredients selected from the groupconsisting of: (i) HMG-CoA reductase inhibitors; (ii) bile acidsequestrants; (iii) niacin and related compounds; (iv) PPARα agonists;(v) cholesterol absorption inhibitors; (vi) acyl CoA:cholesterolacyltransferase (ACAT) inhibitors; (vii) phenolic anti-oxidants; (viii)microsomal triglyceride transfer protein (MTP)/ApoB secretioninhibitors; (ix) anti-oxidant vitamins; (x) thyromimetics; (xi) LDL (lowdensity lipoprotein) receptor inducers; (xii) platelet aggregationinhibitors; (xiii) vitamin B12 (also known as cyanocobalamin); (xiv)folic acid or a pharmaceutically acceptable salt or ester thereof; (xv)FXR and LXR ligands; (xvi) agents that enhance ABCA1 gene expression;and (xvii) ileal bile acid transporters.